Genetic alterations on chromosome 12 and methods of use thereof for the diagnosis and treatment of type 1 diabetes

ABSTRACT

Compositions and methods for the detection and treatment of T1D are provided.

The present application is §371 application of PCT/US2008/056864 filedMar. 13, 2008 which claims priority to U.S. Provisional Application Nos.60/894,649 filed Mar. 13, 2007, 60/910,019 filed Apr. 4, 2007 and60/940,274 filed May 25, 2007, the entire disclosure of each beingincorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to the fields of glucose metabolism, genetics andpathology associated with diabetes, particularly type I diabetes. Morespecifically, the invention provides a panel of genes containing singlenucleotide polymorphisms which had heretofore not been associated withthis disease. Methods and kits for using the sequences so identified fordiagnostic and therapeutic treatment purposes are also provided, as aretherapeutic compositions for management of diabetes.

BACKGROUND OF THE INVENTION

Several publications and patent documents are cited throughout thespecification in order to describe the state of the art to which thisinvention pertains. Each of these citations is incorporated herein byreference as though set forth in full.

Type I diabetes (T1D) results from the autoimmune destruction ofpancreatic beta cells, a process believed to be strongly influenced bymultiple genes and environmental factors. The incidence of T1D has beenincreasing in Western countries and has more than doubled in the UnitedStates over the past 30 years. The disease shows a strong familialcomponent, with first-degree relatives of cases being at 15 timesgreater risk of T1D than a randomly selected member of the generalpopulation and monozygotic twins being concordant for T1D at a frequencyof approximately 50%. However, while the genetic evidence is strong, thelatter data suggests that an interplay with environmental factors alsoplays a key role in influencing T1D outcome.

The familial clustering of T1D is influenced by multiple genes.Variation in four loci has already been established to account for asignificant proportion of the familial aggregation of T1D. These includethe major histocompatibility complex (MHC) region on 6p21 (including theHLA-DRB1, -DQA1 and -DRQ1 genes¹); the insulin/insulin-like growthfactor 2 gene complex (INS-IGF2) on 11p15²⁻⁴, the protein tyrosinephosphatase-22 (PTPN22) gene on 1p13^(5, 6) and the gene encodingcytotoxic T-lymphocyte-associated protein 4 (CTLA4) on 2q31^(7, 8). Theinterleukin-2 receptor alpha (CD25) locus on 10p15⁹ has also beenimplicated in the pathogenesis of T1D but remains to be replicated byindependent studies. In addition, spontaneous mouse model studies of T1Dhave implicated numerous other regions that have been confirmed inreplication studies¹⁰. Several other loci have also been implicated inhuman association studies with T1D but the effects of these implicatedgenes remain controversial and are subject to confirmation inindependent studies utilizing sufficient sample sizes. Together, thesestudies suggest that many more T1D susceptibility genes remain to bediscovered. It is also clear that there are differences in geneticsusceptibility to T1D between populations. An explanation for thisvariation may be related to differing frequencies of T1D causative andprotective variants between different populations and ethnic groups, ahypothesis that needs to be addressed in multi-center, multi-nationalstudies that are truly trans-continental.

SUMMARY OF THE INVENTION

In accordance with the present invention, T1D-associated SNPs have beenidentified which are indicative of an increased or reduced risk ofdeveloping T1D. Thus, in one aspect, nucleic acids comprising at leastone genetic alteration identified in Tables 1-3 are provided. Suchnucleic acids and the proteins encoded thereby have utility in thediagnosis and management of type 1 diabetes (T1D).

In another aspect of the invention, methods for assessing susceptibilityfor developing T1D are provided. An exemplary method entails providing atarget nucleic acid from a patient sample, said target nucleic acidhaving a predetermined sequence in the normal population, and assessingsaid target nucleic acid for the presence of a single nucleotidepolymorphism which is indicative of an increased or decreased risk ofdeveloping T1D. Such genetic alterations include, without limitation,inversion, deletion, duplication, and insertion of at least onenucleotide in said sequence.

Preferably, the genetic alteration is a single nucleotide polymorphismat the 12q13 region of chromosome 12, said SNP being associated withincreased risk of developing T1D. Preferably, the SNP is present onlocus 18 and comprises an allele selected from the group consisting of Gof rs10876864, C of rs1701704 and G of rs773107. These aforementionedSNPs are present on a region of chromosome 12q13 harboring the RAB5B,CDK2, SUOX, IKZF4, RPS26 and ERBB3 genes.

The methods of the invention also include the detection of any of theT1D associated genetic alterations comprising the single nucleotidepolymorphisms set forth in Tables 1-3 for the diagnosis of T1D. Kits andmicroarrays for practicing the foregoing methods are also provided.

In yet another embodiment, a method of managing T1D is provided whichentails administering a therapeutic agent to a patient in need thereof.The therapeutic agent can be a small molecule, an antibody, a protein,an oligonucleotide, or a siRNA molecule.

In another aspect of the invention, a method for identifying agents thatbind and/or modulate RPS26 functional activity is provided, as well aspharmaceutical compositions comprising said agent in a biologicallyacceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Pairwise linkage disequilibrium diagram of the locus on 12q13.This ‘gold plot’ is derived from HapMap CEU data corresponding to aregion spanning from 54567159 (rs12298127) to 54806642 (rs17118317) basepairs on chromosome 12 (Build 35); intensity of shading is proportionalto D′. The relative genomic location of the genes is shown.

FIG. 2. RPS26 sequence located on chromosome 12q13. Both the nucleicacid sequence (SEQ ID NO: 1) in panel A and protein sequence (SEQ ID NO:2) in panel B of RPS26 corresponding to GenBank Accession numberNM_(—)001029 are shown. This sequence is the basis of the candidatesiRNA molecules in Table 9, SEQ ID NOs: 1913-2002.

FIG. 3. CDK2 nucleic acid sequences used to design candidate siRNAmolecules. Panel A shows GenBank Accession number NM_(—)052827 (SEQ IDNO: 3) which corresponds to Table 5, SEQ ID NOs: 12-251, and panel Bshows GenBank Accession number NM_(—)001798 (SEQ ID NO: 4) correspondingto SEQ ID NOs: 252-488 of Table 5.

FIG. 4. ERBB3 nucleic acid sequence used to design candidate siRNAmolecules. Panel A shows GenBank Accession number NM_(—)001005915 (SEQID NO: 5) which corresponds with SEQ ID NOs: 489-568 of Table 6, andpanel B shows GenBank Accession number NM_(—)001982 (SEQ ID NO: 6) whichcorresponds with SEQ ID NOs: 569-1120 of Table 6.

FIG. 5. IKZF4 nucleic acid sequence used to design candidate siRNAmolecules. The figure shows GenBank Accession number NM_(—)022465 (SEQID NO: 7) which corresponds with SEQ ID NOs: 1121-1592 of Table 7.

FIG. 6. RAB5B nucleic acid sequence used to design candidate siRNAmolecules. The figure shows GenBank Accession number NM_(—)002868 (SEQID NO: 8) which corresponds with SEQ ID NO: 1593-1912 of Table 8.

FIG. 7 SUOX nucleic acid sequences used to design candidate siRNAmolecules. Panel A shows GenBank Accession number NM_(—)000456 (SEQ IDNO: 9) which corresponds with SEQ ID NOs: 2003-2204 of Table 10, panel Bshows GenBank Accession number NM_(—)001032386 (SEQ ID NO: 10) whichcorresponds with SEQ ID NOs: 2205-2394 of Table 10, and panel C showsGenBank Accession number NM_(—)001032387 (SEQ ID NO: 11) whichcorresponds with SEQ ID NOs: 2395-2576 of Table 10.

DETAILED DESCRIPTION OF THE INVENTION

A number of genetic determinants of T1D have already been establishedthrough candidate gene studies, primarily with the majorhistocompatibility complex (MHC) but also with other loci. To identifynovel genetic factors that confer risk of T1D, a genome-wide association(GWA) study in a large pediatric study cohort of Western European decentwas performed. In addition to confirming previously identified loci, wealso observed and replicated association to the 12q13 region ofchromosome 12, with increased risk of developing T1D. Three commonnon-coding variants (G of rs10876864, C of rs1701704 and G of rs773107)in strong LD conferred risk for T1D. These SNPs are present on a regionof chromosome 12q13 harboring the RAB5B, CDK2, SUOX, IKZF4, RPS26 andERBB3 genes.

These results provide evidence for a novel genetic factor thatcontributes substantially to the pathogenesis of T1D, including a commonvariant conferring risk for developing disease, and thus providing apromising new T1D therapeutic and diagnostic target.

The following definitions are provided to facilitate an understanding ofthe present invention:

For purposes of the present invention, “a” or “an” entity refers to oneor more of that entity; for example, “a cDNA” refers to one or more cDNAor at least one cDNA. As such, the terms “a” or “an,” “one or more” and“at least one” can be used interchangeably herein. It is also noted thatthe terms “comprising,” “including,” and “having” can be usedinterchangeably. Furthermore, a compound “selected from the groupconsisting of” refers to one or more of the compounds in the list thatfollows, including mixtures (i.e. combinations) of two or more of thecompounds. According to the present invention, an isolated, orbiologically pure molecule is a compound that has been removed from itsnatural milieu. As such, “isolated” and “biologically pure” do notnecessarily reflect the extent to which the compound has been purified.An isolated compound of the present invention can be obtained from itsnatural source, can be produced using laboratory synthetic techniques orcan be produced by any such chemical synthetic route.

A “single nucleotide polymorphism (SNP)” refers to a change in which asingle base in the DNA differs from the usual base at that position.These single base changes are called SNPs or “snips.” Millions of SNP'shave been cataloged in the human genome. Some SNPs such that whichcauses sickle cell are responsible for disease. Other SNPs are normalvariations in the genome.

The term “genetic alteration” as used herein refers to a change from thewild-type or reference sequence of one or more nucleic acid molecules.Genetic alterations include without limitation, base pair substitutions,additions and deletions of at least one nucleotide from a nucleic acidmolecule of known sequence.

The phrase “Type 1 diabetes (T1D)” refers to a chronic (lifelong)disease that occurs when the pancreas produces too little insulin toregulate blood sugar levels appropriately. T1D, often called juvenile orinsulin-dependent diabetes results from altered metabolism ofcarbohydrates (including sugars such as glucose), proteins, and fats. Intype 1 diabetes, the beta cells of the pancreas produce little or noinsulin, the hormone that allows glucose to enter body cells. Onceglucose enters a cell, it is used as fuel. Without adequate insulin,glucose builds up in the bloodstream instead of going into the cells.The body is unable to use this glucose for energy despite high levels inthe bloodstream, leading to increased hunger. In addition, the highlevels of glucose in the blood cause the patient to urinate more, whichin turn causes excessive thirst. Within 5 to 10 years after diagnosis,the insulin-producing beta cells of the pancreas are completelydestroyed, and no more insulin is produced.

“T1D-associated SNP or specific marker” is a SNP or marker which isassociated with an increased or decreased risk of developing T1D notfound normal patients who do not have this disease. Such markers mayinclude but are not limited to nucleic acids, proteins encoded thereby,or other small molecules. Type 1 diabetes can occur at any age, but itusually starts in people younger than 30. Symptoms are usually severeand occur rapidly. The exact cause of type 1 diabetes is not known. Type1 diabetes accounts for 3% of all new cases of diabetes each year. Thereis 1 new case per every 7,000 children per year. New cases are lesscommon among adults older than 20.

The term “solid matrix” as used herein refers to any format, such asbeads, microparticles, a microarray, the surface of a microtitrationwell or a test tube, a dipstick or a filter. The material of the matrixmay be polystyrene, cellulose, latex, nitrocellulose, nylon,polyacrylamide, dextran or agarose. “Sample” or “patient sample” or“biological sample” generally refers to a sample which may be tested fora particular molecule, preferably an T1D specific marker molecule, suchas a marker shown in the tables provided below. Samples may include butare not limited to cells, body fluids, including blood, serum, plasma,urine, saliva, tears, pleural fluid and the like.

The phrase “consisting essentially of” when referring to a particularnucleotide or amino acid means a sequence having the properties of agiven SEQ ID NO. For example, when used in reference to an amino acidsequence, the phrase includes the sequence per se and molecularmodifications that would not affect the functional and novelcharacteristics of the sequence.

“Target nucleic acid” as used herein refers to a previously definedregion of a nucleic acid present in a complex nucleic acid mixturewherein the defined wild-type region contains at least one knownnucleotide variation which may or may not be associated with T1D. Thenucleic acid molecule may be isolated from a natural source by cDNAcloning or subtractive hybridization or synthesized manually. Thenucleic acid molecule may be synthesized manually by the triestersynthetic method or by using an automated DNA synthesizer.

With regard to nucleic acids used in the invention, the term “isolatednucleic acid” is sometimes employed. This term, when applied to DNA,refers to a DNA molecule that is separated from sequences with which itis immediately contiguous (in the 5′ and 3′ directions) in the naturallyoccurring genome of the organism from which it was derived. For example,the “isolated nucleic acid” may comprise a DNA molecule inserted into avector, such as a plasmid or virus vector, or integrated into thegenomic DNA of a prokaryote or eukaryote. An “isolated nucleic acidmolecule” may also comprise a cDNA molecule. An isolated nucleic acidmolecule inserted into a vector is also sometimes referred to herein asa recombinant nucleic acid molecule.

With respect to RNA molecules, the term “isolated nucleic acid”primarily refers to an RNA molecule encoded by an isolated DNA moleculeas defined above. Alternatively, the term may refer to an RNA moleculethat has been sufficiently separated from RNA molecules with which itwould be associated in its natural state (i.e., in cells or tissues),such that it exists in a “substantially pure” form. By the use of theterm “enriched” in reference to nucleic acid it is meant that thespecific DNA or RNA sequence constitutes a significantly higher fraction(2-5 fold) of the total DNA or RNA present in the cells or solution ofinterest than in normal cells or in the cells from which the sequencewas taken. This could be caused by a person by preferential reduction inthe amount of other DNA or RNA present, or by a preferential increase inthe amount of the specific DNA or RNA sequence, or by a combination ofthe two. However, it should be noted that “enriched” does not imply thatthere are no other DNA or RNA sequences present, just that the relativeamount of the sequence of interest has been significantly increased.

It is also advantageous for some purposes that a nucleotide sequence bein purified form. The term “purified” in reference to nucleic acid doesnot require absolute purity (such as a homogeneous preparation);instead, it represents an indication that the sequence is relativelypurer than in the natural environment (compared to the natural level,this level should be at least 2-5 fold greater, e.g., in terms ofmg/ml). Individual clones isolated from a cDNA library may be purifiedto electrophoretic homogeneity. The claimed DNA molecules obtained fromthese clones can be obtained directly from total DNA or from total RNA.The cDNA clones are not naturally occurring, but rather are preferablyobtained via manipulation of a partially purified naturally occurringsubstance (messenger RNA). The construction of a cDNA library from mRNAinvolves the creation of a synthetic substance (cDNA) and pureindividual cDNA clones can be isolated from the synthetic library byclonal selection of the cells carrying the cDNA library. Thus, theprocess which includes the construction of a cDNA library from mRNA andisolation of distinct cDNA clones yields an approximately 10⁻⁶-foldpurification of the native message. Thus, purification of at least oneorder of magnitude, preferably two or three orders, and more preferablyfour or five orders of magnitude is expressly contemplated. Thus, theterm “substantially pure” refers to a preparation comprising at least50-60% by weight the compound of interest (e.g., nucleic acid,oligonucleotide, etc.). More preferably, the preparation comprises atleast 75% by weight, and most preferably 90-99% by weight, the compoundof interest. Purity is measured by methods appropriate for the compoundof interest.

The term “complementary” describes two nucleotides that can formmultiple favorable interactions with one another. For example, adenineis complementary to thymine as they can form two hydrogen bonds.Similarly, guanine and cytosine are complementary since they can formthree hydrogen bonds. Thus if a nucleic acid sequence contains thefollowing sequence of bases, thymine, adenine, guanine and cytosine, a“complement” of this nucleic acid molecule would be a moleculecontaining adenine in the place of thymine, thymine in the place ofadenine, cytosine in the place of guanine, and guanine in the place ofcytosine. Because the complement can contain a nucleic acid sequencethat forms optimal interactions with the parent nucleic acid molecule,such a complement can bind with high affinity to its parent molecule.

With respect to single stranded nucleic acids, particularlyoligonucleotides, the term “specifically hybridizing” refers to theassociation between two single-stranded nucleotide molecules ofsufficiently complementary sequence to permit such hybridization underpre-determined conditions generally used in the art (sometimes termed“substantially complementary”). In particular, the term refers tohybridization of an oligonucleotide with a substantially complementarysequence contained within a single-stranded DNA or RNA molecule of theinvention, to the substantial exclusion of hybridization of theoligonucleotide with single-stranded nucleic acids of non-complementarysequence. For example, specific hybridization can refer to a sequencewhich hybridizes to any T1D specific marker gene or nucleic acid, butdoes not hybridize to other human nucleotides. Also polynucleotide which“specifically hybridizes” may hybridize only to a T1D specific marker,such a T1D-specific marker shown in Tables 1-3. Appropriate conditionsenabling specific hybridization of single stranded nucleic acidmolecules of varying complementarity are well known in the art. Forinstance, one common formula for calculating the stringency conditionsrequired to achieve hybridization between nucleic acid molecules of aspecified sequence homology is set forth below (Sambrook et al.,Molecular Cloning, Cold Spring Harbor Laboratory (1989):T _(m)=81.5° C.+16.6 Log [Na+]+0.41(% G+C)−0.63(% formamide)−600/#bp induplex

As an illustration of the above formula, using [Na+]=[0.368] and 50%formamide, with GC content of 42% and an average probe size of 200bases, the T_(m) is 57° C. The T_(m) of a DNA duplex decreases by 1-1.5°C. with every 1% decrease in homology. Thus, targets with greater thanabout 75% sequence identity would be observed using a hybridizationtemperature of 42° C.

The stringency of the hybridization and wash depend primarily on thesalt concentration and temperature of the solutions. In general, tomaximize the rate of annealing of the probe with its target, thehybridization is usually carried out at salt and temperature conditionsthat are 20-25° C. below the calculated T_(m) of the hybrid. Washconditions should be as stringent as possible for the degree of identityof the probe for the target. In general, wash conditions are selected tobe approximately 12-20° C. below the T_(m) of the hybrid. In regards tothe nucleic acids of the current invention, a moderate stringencyhybridization is defined as hybridization in 6×SSC, 5×Denhardt'ssolution, 0.5% SDS and 100 μg/ml denatured salmon sperm DNA at 42° C.,and washed in 2×SSC and 0.5% SDS at 55° C. for 15 minutes. A highstringency hybridization is defined as hybridization in 6×SSC,5×Denhardt's solution, 0.5% SDS and 100 μg/ml denatured salmon sperm DNAat 42° C., and washed in 1×SSC and 0.5% SDS at 65° C. for 15 minutes. Avery high stringency hybridization is defined as hybridization in 6×SSC,5×Denhardt's solution, 0.5% SDS and 100 μg/ml denatured salmon sperm DNAat 42° C., and washed in 0.1×SSC and 0.5% SDS at 65° C. for 15 minutes.

The term “oligonucleotide” or “oligo” as used herein means a shortsequence of DNA or DNA derivatives typically 8 to 35 nucleotides inlength, primers, or probes. An oligonucleotide can be derivedsynthetically, by cloning or by amplification. An oligo is defined as anucleic acid molecule comprised of two or more ribo- ordeoxyribonucleotides, preferably more than three. The exact size of theoligonucleotide will depend on various factors and on the particularapplication and use of the oligonucleotide. The term “derivative” isintended to include any of the above described variants when comprisingan additional chemical moiety not normally a part of these molecules.These chemical moieties can have varying purposes including, improvingsolubility, absorption, biological half life, decreasing toxicity andeliminating or decreasing undesirable side effects.

The term “probe” as used herein refers to an oligonucleotide,polynucleotide or nucleic acid, either RNA or DNA, whether occurringnaturally as in a purified restriction enzyme digest or producedsynthetically, which is capable of annealing with or specificallyhybridizing to a nucleic acid with sequences complementary to the probe.A probe may be either single-stranded or double-stranded. The exactlength of the probe will depend upon many factors, includingtemperature, source of probe and use of the method. For example, fordiagnostic applications, depending on the complexity of the targetsequence, the oligonucleotide probe typically contains 15-25 or morenucleotides, although it may contain fewer nucleotides. The probesherein are selected to be complementary to different strands of aparticular target nucleic acid sequence. This means that the probes mustbe sufficiently complementary so as to be able to “specificallyhybridize” or anneal with their respective target strands under a set ofpre-determined conditions. Therefore, the probe sequence need notreflect the exact complementary sequence of the target. For example, anon-complementary nucleotide fragment may be attached to the 5′ or 3′end of the probe, with the remainder of the probe sequence beingcomplementary to the target strand. Alternatively, non-complementarybases or longer sequences can be interspersed into the probe, providedthat the probe sequence has sufficient complementarity with the sequenceof the target nucleic acid to anneal therewith specifically.

The term “primer” as used herein refers to an oligonucleotide, eitherRNA or DNA, either single-stranded or double-stranded, either derivedfrom a biological system, generated by restriction enzyme digestion, orproduced synthetically which, when placed in the proper environment, isable to functionally act as an initiator of template-dependent nucleicacid synthesis. When presented with an appropriate nucleic acidtemplate, suitable nucleoside triphosphate precursors of nucleic acids,a polymerase enzyme, suitable cofactors and conditions such as asuitable temperature and pH, the primer may be extended at its 3′terminus by the addition of nucleotides by the action of a polymerase orsimilar activity to yield a primer extension product. The primer mayvary in length depending on the particular conditions and requirement ofthe application. For example, in diagnostic applications, theoligonucleotide primer is typically 15-25 or more nucleotides in length.The primer must be of sufficient complementarity to the desired templateto prime the synthesis of the desired extension product, that is, to beable anneal with the desired template strand in a manner sufficient toprovide the 3′ hydroxyl moiety of the primer in appropriatejuxtaposition for use in the initiation of synthesis by a polymerase orsimilar enzyme. It is not required that the primer sequence represent anexact complement of the desired template. For example, anon-complementary nucleotide sequence may be attached to the 5′ end ofan otherwise complementary primer. Alternatively, non-complementarybases may be interspersed within the oligonucleotide primer sequence,provided that the primer sequence has sufficient complementarity withthe sequence of the desired template strand to functionally provide atemplate-primer complex for the synthesis of the extension product.

Polymerase chain reaction (PCR) has been described in U.S. Pat. Nos.4,683,195, 4,800,195, and 4,965,188, the entire disclosures of which areincorporated by reference herein.

An “siRNA” refers to a molecule involved in the RNA interference processfor a sequence-specific post-transcriptional gene silencing or geneknockdown by providing small interfering RNAs (siRNAs) that has homologywith the sequence of the targeted gene. Small interfering RNAs (siRNAs)can be synthesized in vitro or generated by ribonuclease III cleavagefrom longer dsRNA and are the mediators of sequence-specific mRNAdegradation. Preferably, the siRNA of the invention are chemicallysynthesized using appropriately protected ribonucleosidephosphoramidites and a conventional DNA/RNA synthesizer. The siRNA canbe synthesized as two separate, complementary RNA molecules, or as asingle RNA molecule with two complementary regions. Commercial suppliersof synthetic RNA molecules or synthesis reagents include AppliedBiosystems (Foster City, Calif., USA), Proligo (Hamburg, Germany),Dharmacon Research (Lafayette, Colo., USA), Pierce Chemical (part ofPerbio Science, Rockford, Ill., USA), Glen Research (Sterling, Va.,USA), ChemGenes (Ashland, Mass., USA) and Cruachem (Glasgow, UK).Specific siRNA constructs for inhibiting the mRNA of one of the sixgenes on 12q13, or SNP-containing genes may be between 15-35 nucleotidesin length, and more typically about 21 nucleotides in length. SpecificsiRNA constructs for inhibiting RPS26 mRNA may be between 15-35nucleotides in length, and more typically about 21 nucleotides inlength. A list of candidate siRNAs directed to CDK2 ERBB3, IKZF4, RAB5B,RPS26, and SUOX are provided in Tables 5-10 respectively.

The term “vector” relates to a single or double stranded circularnucleic acid molecule that can be infected, transfected or transformedinto cells and replicate independently or within the host cell genome. Acircular double stranded nucleic acid molecule can be cut and therebylinearized upon treatment with restriction enzymes. An assortment ofvectors, restriction enzymes, and the knowledge of the nucleotidesequences that are targeted by restriction enzymes are readily availableto those skilled in the art, and include any replicon, such as aplasmid, cosmid, bacmid, phage or virus, to which another geneticsequence or element (either DNA or RNA) may be attached so as to bringabout the replication of the attached sequence or element. A nucleicacid molecule of the invention can be inserted into a vector by cuttingthe vector with restriction enzymes and ligating the two piecestogether.

Many techniques are available to those skilled in the art to facilitatetransformation, transfection, or transduction of the expressionconstruct into a prokaryotic or eukaryotic organism. The terms“transformation”, “transfection”, and “transduction” refer to methods ofinserting a nucleic acid and/or expression construct into a cell or hostorganism. These methods involve a variety of techniques, such astreating the cells with high concentrations of salt, an electric field,or detergent, to render the host cell outer membrane or wall permeableto nucleic acid molecules of interest, microinjection,peptide-tethering, PEG-fusion, and the like.

The term “promoter element” describes a nucleotide sequence that isincorporated into a vector that, once inside an appropriate cell, canfacilitate transcription factor and/or polymerase binding and subsequenttranscription of portions of the vector DNA into mRNA. In oneembodiment, the promoter element of the present invention precedes the5′ end of the T1D specific marker nucleic acid molecule such that thelatter is transcribed into mRNA. Host cell machinery then translatesmRNA into a polypeptide.

Those skilled in the art will recognize that a nucleic acid vector cancontain nucleic acid elements other than the promoter element and theT1D specific marker gene nucleic acid molecule. These other nucleic acidelements include, but are not limited to, origins of replication,ribosomal binding sites, nucleic acid sequences encoding drug resistanceenzymes or amino acid metabolic enzymes, and nucleic acid sequencesencoding secretion signals, localization signals, or signals useful forpolypeptide purification.

A “replicon” is any genetic element, for example, a plasmid, cosmid,bacmid, plastid, phage or virus that is capable of replication largelyunder its own control. A replicon may be either RNA or DNA and may besingle or double stranded.

An “expression operon” refers to a nucleic acid segment that may possesstranscriptional and translational control sequences, such as promoters,enhancers, translational start signals (e.g., ATG or AUG codons),polyadenylation signals, terminators, and the like, and which facilitatethe expression of a polypeptide coding sequence in a host cell ororganism.

As used herein, the terms “reporter,” “reporter system”, “reportergene,” or “reporter gene product” shall mean an operative genetic systemin which a nucleic acid comprises a gene that encodes a product thatwhen expressed produces a reporter signal that is a readily measurable,e.g., by biological assay, immunoassay, radio immunoassay, or bycolorimetric, fluorogenic, chemiluminescent or other methods. Thenucleic acid may be either RNA or DNA, linear or circular, single ordouble stranded, antisense or sense polarity, and is operatively linkedto the necessary control elements for the expression of the reportergene product. The required control elements will vary according to thenature of the reporter system and whether the reporter gene is in theform of DNA or RNA, but may include, but not be limited to, suchelements as promoters, enhancers, translational control sequences, polyA addition signals, transcriptional termination signals and the like.

The introduced nucleic acid may or may not be integrated (covalentlylinked) into nucleic acid of the recipient cell or organism. Inbacterial, yeast, plant and mammalian cells, for example, the introducednucleic acid may be maintained as an episomal element or independentreplicon such as a plasmid. Alternatively, the introduced nucleic acidmay become integrated into the nucleic acid of the recipient cell ororganism and be stably maintained in that cell or organism and furtherpassed on or inherited to progeny cells or organisms of the recipientcell or organism. Finally, the introduced nucleic acid may exist in therecipient cell or host organism only transiently.

The term “selectable marker gene” refers to a gene that when expressedconfers a selectable phenotype, such as antibiotic resistance, on atransformed cell.

The term “operably linked” means that the regulatory sequences necessaryfor expression of the coding sequence are placed in the DNA molecule inthe appropriate positions relative to the coding sequence so as toeffect expression of the coding sequence. This same definition issometimes applied to the arrangement of transcription units and othertranscription control elements (e.g. enhancers) in an expression vector.

The terms “recombinant organism,” or “transgenic organism” refer toorganisms which have a new combination of genes or nucleic acidmolecules. A new combination of genes or nucleic acid molecules can beintroduced into an organism using a wide array of nucleic acidmanipulation techniques available to those skilled in the art. The term“organism” relates to any living being comprised of a least one cell. Anorganism can be as simple as one eukaryotic cell or as complex as amammal. Therefore, the phrase “a recombinant organism” encompasses arecombinant cell, as well as eukaryotic and prokaryotic organism.

The term “isolated protein” or “isolated and purified protein” issometimes used herein. This term refers primarily to a protein producedby expression of an isolated nucleic acid molecule of the invention.Alternatively, this term may refer to a protein that has beensufficiently separated from other proteins with which it would naturallybe associated, so as to exist in “substantially pure” form. “Isolated”is not meant to exclude artificial or synthetic mixtures with othercompounds or materials, or the presence of impurities that do notinterfere with the fundamental activity, and that may be present, forexample, due to incomplete purification, addition of stabilizers, orcompounding into, for example, immunogenic preparations orpharmaceutically acceptable preparations.

A “specific binding pair” comprises a specific binding member (sbm) anda binding partner (bp) which have a particular specificity for eachother and which in normal conditions bind to each other in preference toother molecules. Examples of specific binding pairs are antigens andantibodies, ligands and receptors and complementary nucleotidesequences. The skilled person is aware of many other examples. Further,the term “specific binding pair” is also applicable where either or bothof the specific binding member and the binding partner comprise a partof a large molecule. In embodiments in which the specific binding paircomprises nucleic acid sequences, they will be of a length to hybridizeto each other under conditions of the assay, preferably greater than 10nucleotides long, more preferably greater than 15 or 20 nucleotideslong. “Sample” or “patient sample” or “biological sample” generallyrefers to a sample which may be tested for a particular molecule,preferably a T1D specific marker molecule, such as a marker shown inTables 1-3. Samples may include but are not limited to cells, bodyfluids, including blood, serum, plasma, urine, saliva, tears, pleuralfluid and the like.

The terms “agent” and “test compound” are used interchangeably hereinand denote a chemical compound, a mixture of chemical compounds, abiological macromolecule, or an extract made from biological materialssuch as bacteria, plants, fungi, or animal (particularly mammalian)cells or tissues. Biological macromolecules include siRNA, shRNA,antisense oligonucleotides, small molecules, antibodies, peptides,peptide/DNA complexes, and any nucleic acid based molecule, for examplean oligo, which exhibits the capacity to modulate the activity of theSNP containing nucleic acids described herein or their encoded proteins.Agents are evaluated for potential biological activity by inclusion inscreening assays described herein below.

The term “modulate” as used herein refers increasing or decreasing. Forexample, the term modulate refers to the ability of a compound or testagent to interfere with signaling or activity of a gene or protein ofthe present invention. Therefore, modulating the signaling mediated byRPS26 means that an agent or compound inhibits or enhances the activityof the proteins encoded by the gene. This includes altering the activityof natural killer cells, and preventing autoimmune beta celldestruction.

Methods of Using T1D-Associated SNPS for T1D Detection Assays

T1D SNP containing nucleic acids, including but not limited to thoselisted in Tables 1-3, may be used for a variety of purposes inaccordance with the present invention. T1D-associated SNP containingDNA, RNA, or fragments thereof may be used as probes to detect thepresence of and/or expression of T1D specific markers. Methods in whichT1D specific marker nucleic acids may be utilized as probes for suchassays include, but are not limited to: (1) in situ hybridization; (2)Southern hybridization (3) northern hybridization; and (4) assortedamplification reactions such as polymerase chain reactions (PCR).

Further, assays for detecting T1D-associated SNPs may be conducted onany type of biological sample, including but not limited to body fluids(including blood, urine, serum, gastric lavage), any type of cell (suchas white blood cells, mononuclear cells) or body tissue.

From the foregoing discussion, it can be seen that T1D associated SNPcontaining nucleic acids, vectors expressing the same, T1D SNPcontaining marker proteins and anti-T1D specific marker antibodies ofthe invention can be used to detect T1D associated SNPs in body tissue,cells, or fluid, and alter T1D SNP containing marker protein expressionfor purposes of assessing the genetic and protein interactions involvedin T1D.

In most embodiments for screening for T1D-associated SNPs, theT1D-associated SNP containing nucleic acid in the sample will initiallybe amplified, e.g. using PCR, to increase the amount of the template ascompared to other sequences present in the sample. This allows thetarget sequences to be detected with a high degree of sensitivity ifthey are present in the sample. This initial step may be avoided byusing highly sensitive array techniques that are becoming increasinglyimportant in the art.

Alternatively, new detection technologies can overcome this limitationand enable analysis of small samples containing as little as 1 μg oftotal RNA. Using Resonance Light Scattering (RLS) technology, as opposedto traditional fluorescence techniques, multiple reads can detect lowquantities of mRNAs using biotin labeled hybridized targets andanti-biotin antibodies. Another alternative to PCR amplificationinvolves planar wave guide technology (PWG) to increase signal-to-noiseratios and reduce background interference. Both techniques arecommercially available from Qiagen Inc. (USA).

Thus, any of the aforementioned techniques may be used to detect orquantify T1D-associated SNP marker expression and accordingly, detectpatient susceptibility for developing T1D.

Kits and Articles of Manufacture

Any of the aforementioned products can be incorporated into a kit whichmay contain an T1D-associated SNP specific marker polynucleotide or oneor more such markers immobilized on a Gene Chip, an oligonucleotide, apolypeptide, a peptide, an antibody, a label, marker, or reporter, apharmaceutically acceptable carrier, a physiologically acceptablecarrier, instructions for use, a container, a vessel for administration,an assay substrate, or any combination thereof.

Methods of Using T1D-Associated SNPS for Development of TherapeuticAgents

Since the SNPs identified herein have been associated with the etiologyof T1D, methods for identifying agents that modulate the activity of thegenes and their encoded products containing such SNPs should result inthe generation of efficacious therapeutic agents for the treatment of avariety of disorders associated with this condition.

Chromosome 12 contains regions which provide suitable targets for therational design of therapeutic agents which modulate their activity.Small peptide molecules corresponding to these regions may be used toadvantage in the design of therapeutic agents which effectively modulatethe activity of the encoded proteins.

Molecular modeling should facilitate the identification of specificorganic molecules with capacity to bind to the active site of theproteins encoded by the SNP containing nucleic acids based onconformation or key amino acid residues required for function. Acombinatorial chemistry approach will be used to identify molecules withgreatest activity and then iterations of these molecules will bedeveloped for further cycles of screening.

The polypeptides or fragments employed in drug screening assays mayeither be free in solution, affixed to a solid support or within a cell.One method of drug screening utilizes eukaryotic or prokaryotic hostcells which are stably transformed with recombinant polynucleotidesexpressing the polypeptide or fragment, preferably in competitivebinding assays. Such cells, either in viable or fixed form, can be usedfor standard binding assays. One may determine, for example, formationof complexes between the polypeptide or fragment and the agent beingtested, or examine the degree to which the formation of a complexbetween the polypeptide or fragment and a known substrate is interferedwith by the agent being tested.

Another technique for drug screening provides high throughput screeningfor compounds having suitable binding affinity for the encodedpolypeptides and is described in detail in Geysen, PCT publishedapplication WO 84/03564, published on Sep. 13, 1984. Briefly stated,large numbers of different, small peptide test compounds, such as thosedescribed above, are synthesized on a solid substrate, such as plasticpins or some other surface. The peptide test compounds are reacted withthe target polypeptide and washed. Bound polypeptide is then detected bymethods well known in the art.

A further technique for drug screening involves the use of hosteukaryotic cell lines or cells (such as described above) which have anonfunctional or altered T1D associated gene. These host cell lines orcells are defective at the polypeptide level. The host cell lines orcells are grown in the presence of drug compound. The rate of cellularmetabolism of the host cells is measured to determine if the compound iscapable of regulating cellular metabolism in the defective cells. Hostcells contemplated for use in the present invention include but are notlimited to bacterial cells, fungal cells, insect cells, mammalian cells,and plant cells. The T1D-associated SNP encoding DNA molecules may beintroduced singly into such host cells or in combination to assess thephenotype of cells conferred by such expression. Methods for introducingDNA molecules are also well known to those of ordinary skill in the art.Such methods are set forth in Ausubel et al. eds., Current Protocols inMolecular Biology, John Wiley & Sons, NY, N.Y. 1995, the disclosure ofwhich is incorporated by reference herein.

Cells and cell lines suitable for studying the effects of the SNPencoding nucleic acids on glucose metabolism and methods of use thereoffor drug discovery are provided. Such cells and cell lines will betransfected with the SNP encoding nucleic acids described herein and theeffects on glucagon secretion, insulin secretion and/or beta cellapoptosis can be determined. Such cells and cell lines will also becontacted with the siRNA molecules provided herein to assess the effectsthereof on glucagon secretion, insulin secretion and/or beta cellapoptosis. The siRNA molecules will be tested alone and in combinationof 2, 3, 4, and 5 siRNAs to identify the most efficacious combinationfor down regulating the gene targets comprising the SNPs describedherein (e.g., RAB5B, CDK2, SUOX, IKZF4, RPS26 and ERBB3). Cells suitablefor these purposes include, without limitation, INS cells (ATCC CRL11605), PC12 cells (ATCC CRL 1721), MIN6 cells, alpha-TC6 cells andINS-1 832/13 cells (Fernandez et al., J. of Proteome Res. (2007).7:400-411). Pancreatic islet cells can be isolated and cultured asdescribed in Joseph, J. et al., (J. Biol. Chem. (2004) 279:51049). Diaoet al. (J. Biol. Chem. (2005) 280:33487-33496), provide methodology forassessing the effects of the SNP encoding nucleic acids and/or thesiRNAs provided herein on glucagon secretion and insulin secretion.Park, J. et al. (J. of Bioch. and Mol. Biol. (2007) 40:1058-68) providemethodology for assessing the effect of these nucleic acid molecules onglucosamine induced beta cell apoptosis in pancreatic islet cells.

A wide variety of expression vectors are available that can be modifiedto express the novel DNA or RNA sequences of this invention. Thespecific vectors exemplified herein are merely illustrative, and are notintended to limit the scope of the invention. Expression methods aredescribed by Sambrook et al. Molecular Cloning: A Laboratory Manual orCurrent Protocols in Molecular Biology 16.3-17.44 (1989). Expressionmethods in Saccharomyces are also described in Current Protocols inMolecular Biology (1989).

Suitable vectors for use in practicing the invention include prokaryoticvectors such as the pNH vectors (Stratagene Inc., 11099 N. Torrey PinesRd., La Jolla, Calif. 92037), pET vectors (Novogen Inc., 565 ScienceDr., Madison, Wis. 53711) and the pGEX vectors (Pharmacia LKBBiotechnology Inc., Piscataway, N.J. 08854). Examples of eukaryoticvectors useful in practicing the present invention include the vectorspRc/CMV, pRc/RSV, and pREP (Invitrogen, 11588 Sorrento Valley Rd., SanDiego, Calif. 92121); pcDNA3.1/V5&H is (Invitrogen); baculovirus vectorssuch as pVL1392, pVL1393, or pAC360 (Invitrogen); and yeast vectors suchas YRP17, YIPS, and YEP24 (New England Biolabs, Beverly, Mass.), as wellas pRS403 and pRS413 Stratagene Inc.); Picchia vectors such as pHIL-D1(Phillips Petroleum Co., Bartlesville, Okla. 74004); retroviral vectorssuch as PLNCX and pLPCX (Clontech); and adenoviral and adeno-associatedviral vectors.

Promoters for use in expression vectors of this invention includepromoters that are operable in prokaryotic or eukaryotic cells.Promoters that are operable in prokaryotic cells include lactose (lac)control elements, bacteriophage lambda (pL) control elements, arabinosecontrol elements, tryptophan (trp) control elements, bacteriophage T7control elements, and hybrids thereof. Promoters that are operable ineukaryotic cells include Epstein Barr virus promoters, adenoviruspromoters, SV40 promoters, Rous Sarcoma Virus promoters, cytomegalovirus(CMV) promoters, baculovirus promoters such as AcMNPV polyhedrinpromoter, Picchia promoters such as the alcohol oxidase promoter, andSaccharomyces promoters such as the gal4 inducible promoter and the PGKconstitutive promoter, as well as neuronal-specific platelet-derivedgrowth factor promoter (PDGF), the Thy-1 promoter, the hamster and mousePrion promoter (MoPrP), and the Glial fibrillar acidic protein (GFAP)for the expression of transgenes in glial cells.

In addition, a vector of this invention may contain any one of a numberof various markers facilitating the selection of a transformed hostcell. Such markers include genes associated with temperaturesensitivity, drug resistance, or enzymes associated with phenotypiccharacteristics of the host organisms.

Host cells expressing the T1D-associated SNPs of the present inventionor functional fragments thereof provide a system in which to screenpotential compounds or agents for the ability to modulate thedevelopment of T1D. Thus, in one embodiment, the nucleic acid moleculesof the invention may be used to create recombinant cell lines for use inassays to identify agents which modulate aspects of lectin binding. Alsoprovided herein are methods to screen for compounds capable ofmodulating the function of proteins encoded by the SNP containingnucleic acids described below.

Another approach entails the use of phage display libraries engineeredto express fragment of the polypeptides encoded by the SNP containingnucleic acids on the phage surface. Such libraries are then contactedwith a combinatorial chemical library under conditions wherein bindingaffinity between the expressed peptide and the components of thechemical library may be detected. U.S. Pat. Nos. 6,057,098 and 5,965,456provide methods and apparatus for performing such assays.

The goal of rational drug design is to produce structural analogs ofbiologically active polypeptides of interest or of small molecules withwhich they interact (e.g., agonists, antagonists, inhibitors) in orderto fashion drugs which are, for example, more active or stable forms ofthe polypeptide, or which, e.g., enhance or interfere with the functionof a polypeptide in vivo. See, e.g., Hodgson, (1991) Bio/Technology9:19-21. In one approach, discussed above, the three-dimensionalstructure of a protein of interest or, for example, of theprotein-substrate complex, is solved by x-ray crystallography, bynuclear magnetic resonance, by computer modeling or most typically, by acombination of approaches. Less often, useful information regarding thestructure of a polypeptide may be gained by modeling based on thestructure of homologous proteins. An example of rational drug design isthe development of HIV protease inhibitors (Erickson et al., (1990)Science 249:527-533). In addition, peptides may be analyzed by analanine scan (Wells, (1991) Meth. Enzym. 202:390-411). In thistechnique, an amino acid residue is replaced by Ala, and its effect onthe peptide's activity is determined. Each of the amino acid residues ofthe peptide is analyzed in this manner to determine the importantregions of the peptide.

It is also possible to isolate a target-specific antibody, selected by afunctional assay, and then to solve its crystal structure. In principle,this approach yields a pharmacophore upon which subsequent drug designcan be based.

One can bypass protein crystallography altogether by generatinganti-idiotypic antibodies (anti-ids) to a functional, pharmacologicallyactive antibody. As a mirror image of a mirror image, the binding siteof the anti-ids would be expected to be an analog of the originalmolecule. The anti-id could then be used to identify and isolatepeptides from banks of chemically or biologically produced banks ofpeptides. Selected peptides would then act as the pharmacophore.

Thus, one may design drugs which have, e.g., improved polypeptideactivity or stability or which act as inhibitors, agonists, antagonists,etc. of polypeptide activity. By virtue of the availability of SNPcontaining nucleic acid sequences described herein, sufficient amountsof the encoded polypeptide may be made available to perform suchanalytical studies as x-ray crystallography. In addition, the knowledgeof the protein sequence provided herein will guide those employingcomputer modeling techniques in place of, or in addition to x-raycrystallography.

In another embodiment, the availability of T1D-associated SNP containingnucleic acids enables the production of strains of laboratory micecarrying the T1D-associated SNPs of the invention. Transgenic miceexpressing the T1D-associated SNP of the invention provide a modelsystem in which to examine the role of the protein encoded by the SNPcontaining nucleic acid in the development and progression towards T1D.Methods of introducing transgenes in laboratory mice are known to thoseof skill in the art. Three common methods include: (1) integration ofretroviral vectors encoding the foreign gene of interest into an earlyembryo; (2) injection of DNA into the pronucleus of a newly fertilizedegg; and (3) the incorporation of genetically manipulated embryonic stemcells into an early embryo. Production of the transgenic mice describedabove will facilitate the molecular elucidation of the role that atarget protein plays in various cellular metabolic processes, including:aberrant lipid deposition, altered cellular metabolism and glucoseregulation. Such mice provide an in vivo screening tool to studyputative therapeutic drugs in a whole animal model and are encompassedby the present invention.

The term “animal” is used herein to include all vertebrate animals,except humans. It also includes an individual animal in all stages ofdevelopment, including embryonic and fetal stages. A “transgenic animal”is any animal containing one or more cells bearing genetic informationaltered or received, directly or indirectly, by deliberate geneticmanipulation at the subcellular level, such as by targeted recombinationor microinjection or infection with recombinant virus. The term“transgenic animal” is not meant to encompass classical cross-breedingor in vitro fertilization, but rather is meant to encompass animals inwhich one or more cells are altered by or receive a recombinant DNAmolecule. This molecule may be specifically targeted to a definedgenetic locus, be randomly integrated within a chromosome, or it may beextrachromosomally replicating DNA. The term “germ cell line transgenicanimal” refers to a transgenic animal in which the genetic alteration orgenetic information was introduced into a germ line cell, therebyconferring the ability to transfer the genetic information to offspring.If such offspring, in fact, possess some or all of that alteration orgenetic information, then they, too, are transgenic animals.

The alteration of genetic information may be foreign to the species ofanimal to which the recipient belongs, or foreign only to the particularindividual recipient, or may be genetic information already possessed bythe recipient. In the last case, the altered or introduced gene may beexpressed differently than the native gene. Such altered or foreigngenetic information would encompass the introduction of T1D-associatedSNP containing nucleotide sequences.

The DNA used for altering a target gene may be obtained by a widevariety of techniques that include, but are not limited to, isolationfrom genomic sources, preparation of cDNAs from isolated mRNA templates,direct synthesis, or a combination thereof.

A preferred type of target cell for transgene introduction is theembryonal stem cell (ES). ES cells may be obtained from pre-implantationembryos cultured in vitro (Evans et al., (1981) Nature 292:154-156;Bradley et al., (1984) Nature 309:255-258; Gossler et al., (1986) Proc.Natl. Acad. Sci. 83:9065-9069). Transgenes can be efficiently introducedinto the ES cells by standard techniques such as DNA transfection or byretrovirus-mediated transduction. The resultant transformed ES cells canthereafter be combined with blastocysts from a non-human animal. Theintroduced ES cells thereafter colonize the embryo and contribute to thegerm line of the resulting chimeric animal.

One approach to the problem of determining the contributions ofindividual genes and their expression products is to use isolatedT1D-associated SNP genes as insertional cassettes to selectivelyinactivate a wild-type gene in totipotent ES cells (such as thosedescribed above) and then generate transgenic mice. The use ofgene-targeted ES cells in the generation of gene-targeted transgenicmice was described, and is reviewed elsewhere (Frohman et al., (1989)Cell 56:145-147; Bradley et al., (1992) Bio/Technology 10:534-539).

Techniques are available to inactivate or alter any genetic region to amutation desired by using targeted homologous recombination to insertspecific changes into chromosomal alleles. However, in comparison withhomologous extrachromosomal recombination, which occurs at a frequencyapproaching 100%, homologous plasmid-chromosome recombination wasoriginally reported to only be detected at frequencies between 10⁻⁶ and10⁻³. Nonhomologous plasmid-chromosome interactions are more frequentoccurring at levels 10⁵-fold to 10² fold greater than comparablehomologous insertion.

To overcome this low proportion of targeted recombination in murine EScells, various strategies have been developed to detect or select rarehomologous recombinants. One approach for detecting homologousalteration events uses the polymerase chain reaction (PCR) to screenpools of transformant cells for homologous insertion, followed byscreening of individual clones. Alternatively, a positive geneticselection approach has been developed in which a marker gene isconstructed which will only be active if homologous insertion occurs,allowing these recombinants to be selected directly. One of the mostpowerful approaches developed for selecting homologous recombinants isthe positive-negative selection (PNS) method developed for genes forwhich no direct selection of the alteration exists. The PNS method ismore efficient for targeting genes which are not expressed at highlevels because the marker gene has its own promoter. Non-homologousrecombinants are selected against by using the Herpes Simplex virusthymidine kinase (HSV-TK) gene and selecting against its nonhomologousinsertion with effective herpes drugs such as gancyclovir (GANC) or(1-(2-deoxy-2-fluoro-B-D arabinofluranosyl)-5-iodou-racil, (FIAU). Bythis counter selection, the number of homologous recombinants in thesurviving transformants can be increased. Utilizing T1D-associated SNPcontaining nucleic acid as a targeted insertional cassette providesmeans to detect a successful insertion as visualized, for example, byacquisition of immunoreactivity to an antibody immunologically specificfor the polypeptide encoded by T1D-associated SNP nucleic acid and,therefore, facilitates screening/selection of ES cells with the desiredgenotype.

As used herein, a knock-in animal is one in which the endogenous murinegene, for example, has been replaced with human T1D-associated SNPcontaining gene of the invention. Such knock-in animals provide an idealmodel system for studying the development of T1D.

As used herein, the expression of a T1D-associated SNP containingnucleic acid, fragment thereof, or a T1D-associated SNP fusion proteincan be targeted in a “tissue specific manner” or “cell type specificmanner” using a vector in which nucleic acid sequences encoding all or aportion of T1D-associated SNP are operably linked to regulatorysequences (e.g., promoters and/or enhancers) that direct expression ofthe encoded protein in a particular tissue or cell type. Such regulatoryelements may be used to advantage for both in vitro and in vivoapplications. Promoters for directing tissue specific expression ofproteins are well known in the art and described herein.

The nucleic acid sequence encoding the T1D-associated SNP of theinvention may be operably linked to a variety of different promotersequences for expression in transgenic animals. Such promoters include,but are not limited to a prion gene promoter such as hamster and mousePrion promoter (MoPrP), described in U.S. Pat. No. 5,877,399 and inBorchelt et al., Genet. Anal. 13(6) (1996) pages 159-163; a rat neuronalspecific enolase promoter, described in U.S. Pat. Nos. 5,612,486, and5,387,742; a platelet-derived growth factor B gene promoter, describedin U.S. Pat. No. 5,811,633; a brain specific dystrophin promoter,described in U.S. Pat. No. 5,849,999; a Thy-1 promoter; a PGK promoter;a CMV promoter; a neuronal-specific platelet-derived growth factor Bgene promoter; and Glial fibrillar acidic protein (GFAP) promoter forthe expression of transgenes in glial cells.

Methods of use for the transgenic mice of the invention are alsoprovided herein. Transgenic mice into which a nucleic acid containingthe T1D-associated SNP or its encoded protein have been introduced areuseful, for example, to develop screening methods to screen therapeuticagents to identify those capable of modulating the development of T1D.

Pharmaceuticals and Peptide Therapies

The elucidation of the role played by the T1D associated SNPs describedherein in cellular metabolism facilitates the development ofpharmaceutical compositions useful for treatment and diagnosis of T1D.These compositions may comprise, in addition to one of the abovesubstances, a pharmaceutically acceptable excipient, carrier, buffer,stabilizer or other materials well known to those skilled in the art.Such materials should be non-toxic and should not interfere with theefficacy of the active ingredient.

Whether it is a polypeptide, antibody, peptide, nucleic acid molecule,small molecule or other pharmaceutically useful compound according tothe present invention that is to be given to an individual,administration is preferably in a “prophylactically effective amount” ora “therapeutically effective amount” (as the case may be, althoughprophylaxis may be considered therapy), this being sufficient to showbenefit to the individual.

As it is presently understood, RNA interference involves a multi-stepprocess. Double stranded RNAs are cleaved by the endonuclease Dicer togenerate nucleotide fragments (siRNA). The siRNA duplex is resolved into2 single stranded RNAs, one strand being incorporated into aprotein-containing complex where it functions as guide RNA to directcleavage of the target RNA (Schwarz et al, Mol. Cell. 10:537 548 (2002),Zamore et al, Cell 101:25 33 (2000)), thus silencing a specific geneticmessage (see also Zeng et al, Proc. Natl. Acad. Sci. 100:9779 (2003)).

The invention includes a method of treating T1D in a mammal. Preferably,the mammal is a human, and the term “patient” as used herein refers to ahuman. An exemplary method entails administering to the mammal apharmaceutically effective amount of siRNA directed to SNP sequences ina patient. The following discussion focuses on RPS26, but should beconstrued to also include siRNA directed to CDK2, ERBB3, IKZF4, RAB5B,and SUOX, all of which are considered for siRNA inhibition using theconstructs in Tables 5-10. The siRNA inhibits the expression of wildtype or variant-SNP-containing RPS26 sequences.

Specific siRNA preparations directed at inhibiting the expression ofRPS26 or variant SNP-containing RPS26, as well as delivery methods areprovided as a novel therapy to treat T1D. SiRNA oligonucleotidesdirected to RPS26 sequences specifically hybridize with nucleic acidsencoding RPS26 and interfere with RPS26 gene expression. The siRNA canbe delivered to a patient in vivo either systemically or locally withcarriers, as discussed below. The compositions of the invention may beused alone or in combination with other agents or genes encodingproteins to augment the efficacy of the compositions.

A “membrane permeant peptide sequence” refers to a peptide sequencewhich is able to facilitate penetration and entry of the RPS26 inhibitoracross the cell membrane. Exemplary peptides include with outlimitation, the signal sequence from Karposi fibroblast growth factorexemplified herein, the HIV tat peptide (Vives et al., J. Biol. Chem.,272:16010-16017, 1997), Nontoxic membrane translocation peptide fromprotamine (Park et al., FASEB J. 19(11):1555-7, 2005), CHARIOTS deliveryreagent (Active Motif; U.S. Pat. No. 6,841,535) and the antimicrobialpeptide Buforin 2.

In one embodiment of the invention siRNAs are delivered for therapeuticbenefit. There are several ways to administer the siRNA of the inventionto in vivo to treat T1D including, but not limited to, naked siRNAdelivery, siRNA conjugation and delivery, liposome carrier-mediateddelivery, polymer carrier delivery, nanoparticle compositions,plasmid-based methods, and the use of viruses.

siRNA composition of the invention can comprise a delivery vehicle,including liposomes, for administration to a subject, carriers anddiluents and their salts, and/or can be present in pharmaceuticallyacceptable formulations. This can be necessary to allow the siRNA tocross the cell membrane and escape degradation. Methods for the deliveryof nucleic acid molecules are described in Akhtar et al., 1992, TrendsCell Bio., 2, 139; Delivery Strategies for Antisense OligonucleotideTherapeutics, ed. Akhtar, 1995, Maurer et al., 1999, Mol. Membr. Biol.,16, 129-140; Hofland and Huang, 1999, Handb. Exp. Pharmacol., 137,165-192; and Lee et al., 2000, ACS Symp. Ser., 752, 184-192; Beigelmanet al., U.S. Pat. No. 6,395,713 and Sullivan et al., PCT WO 94/02595further describe the general methods for delivery of nucleic acidmolecules. These protocols can be utilized for the delivery of virtuallyany nucleic acid molecule.

The frequency of administration of the siRNA to a patient will also varydepending on several factors including, but not limited to, the type andseverity of the T1D to be treated, the route of administration, the ageand overall health of the individual, the nature of the siRNA, and thelike. It is contemplated that the frequency of administration of thesiRNA to the patient may vary from about once every few months to aboutonce a month, to about once a week, to about once per day, to aboutseveral times daily.

Pharmaceutical compositions that are useful in the methods of theinvention may be administered systemically in parenteral, oral solid andliquid formulations, ophthalmic, suppository, aerosol, topical or othersimilar formulations. In addition to the appropriate siRNA, thesepharmaceutical compositions may contain pharmaceutically-acceptablecarriers and other ingredients known to enhance and facilitate drugadministration. Thus such compositions may optionally contain othercomponents, such as adjuvants, e.g., aqueous suspensions of aluminum andmagnesium hydroxides, and/or other pharmaceutically acceptable carriers,such as saline. Other possible formulations, such as nanoparticles,liposomes, resealed erythrocytes, and immunologically based systems mayalso be used to administer the appropriate siRNA to a patient accordingto the methods of the invention. The use of nanoparticles to deliversiRNAs, as well as cell membrane permeable peptide carriers that can beused are described in Crombez et al., Biochemical Society Transactionsv35:p44 (2007).

Methods of the invention directed to treating T1D involve theadministration of RPS26 siRNA in a pharmaceutical composition. RPS26siRNA is administered to an individual as a pharmaceutical compositioncomprising RPS26 siRNA and a pharmaceutically acceptable carrier.Pharmaceutically acceptable carriers are well known in the art andinclude aqueous solutions such as physiologically buffered saline, othersolvents or vehicles such as glycols, glycerol, oils such as olive oilor injectable organic esters.

A pharmaceutically acceptable carrier can contain physiologicallyacceptable compounds that act, for example, to stabilize the RPS26 siRNAor increase the absorption of the agent. Such physiologically acceptablecompounds include, for example, carbohydrates, such as glucose, sucroseor dextrans, antioxidants, such as ascorbic acid or glutathione,chelating agents, low molecular weight proteins or other stabilizers orexcipients. One skilled in the art would know that the choice of apharmaceutically acceptable carrier, including a physiologicallyacceptable compound, depends, for example, on the route ofadministration of the RPS26 siRNA.

One skilled in the art appreciates that a pharmaceutical compositioncomprising RPS26 siRNA can be administered to a subject by variousroutes including, for example, orally or parenterally, such asintravenously (i.v.), intramuscularly, subcutaneously, intraorbitally,intranasally, intracapsularly, intraperitoneally (i.p.),intracisternally, intra-tracheally (i.t.), or intra-articularly or bypassive or facilitated absorption. The same routes of administration canbe used other pharmaceutically useful compounds, for example, smallmolecules, nucleic acid molecules, peptides, antibodies and polypeptidesas discussed herein.

A pharmaceutical composition comprising RPS26 siRNA inhibitor also canbe incorporated, if desired, into liposomes, microspheres, microbubbles,or other polymer matrices (Gregoriadis, Liposome Technology, Vols. I toIII, 2nd ed., CRC Press, Boca Raton Fla. (1993)). Liposomes, forexample, which consist of phospholipids or other lipids, are nontoxic,physiologically acceptable and metabolizable carriers that arerelatively simple to make and administer.

The pharmaceutical preparation comprises a siRNA targeting RPS26 or anexpression vector encoding for an siRNA targeting RPS26 orSNP-containing RPS26. Such pharmaceutical preparations can beadministered to a patient for treating T1D.

Expression vectors for the expression of siRNA molecules preferablyemploy a strong promoter which may be constitutive or regulated. Suchpromoters are well known in the art and include, but are not limited to,RNA polymerase II promoters, the T7 RNA polymerase promoter, and the RNApolymerase III promoters U6 and H1 (see, e.g., Myslinski et al. (2001)Nucl. Acids Res., 29:2502 09).

A formulated siRNA composition can be a composition comprising one ormore siRNA molecules or a vector encoding one or more siRNA moleculesindependently or in combination with a cationic lipid, a neutral lipid,and/or a polyethyleneglycol-diacylglycerol (PEG-DAG) or PEG-cholesterol(PEG-Chol) conjugate. Non-limiting examples of expression vectors aredescribed in Paul et al., 2002, Nature Biotechnology, 19, 505; Miyagishiand Taira, 2002, Nature Biotechnology, 19, 497; Lee et al., 2002, NatureBiotechnology, 19, 500-505.

A lipid nanoparticle composition is a composition comprising one or morebiologically active molecules independently or in combination with acationic lipid, a neutral lipid, and/or apolyethyleneglycol-diacylglycerol (i.e., polyethyleneglycoldiacylglycerol (PEG-DAG), PEG-cholesterol, or PEG-DMB) conjugate. In oneembodiment, the biologically active molecule is encapsulated in thelipid nanoparticle as a result of the process of providing and aqueoussolution comprising a biologically active molecule of the invention(i.e., siRNA), providing an organic solution comprising lipidnanoparticle, mixing the two solutions, incubating the solutions,dilution, ultrafiltration, resulting in concentrations suitable toproduce nanoparticle compositions.

Nucleic acid molecules can be administered to cells by incorporationinto other vehicles, such as biodegradable polymers, hydrogels,cyclodextrins. (see for example Gonzalez et al., 1999, BioconjugateChem., 10, 1068-1074; Wang et al., International PCT publication Nos. WO03/47518 and WO 03/46185), poly(lactic-co-glycolic)acid (PLGA) and PLCAmicrospheres (see for example U.S. Pat. No. 6,447,796 and US PatentApplication Publication No. US 2002130430), biodegradable nanocapsules,and bioadhesive microspheres, or by proteinaceous vectors (O'Hare andNormand, International PCT Publication No. WO 00/53722)

Cationic lipids and polymers are two classes of non-viral siRNA deliverywhich can form complexes with negatively charged siRNA. Theself-assembly PEG-ylated polycation polyethylenimine (PEI) has also beenused to condense and protect siRNAs (Schiffelers et al., 2004, Nuc.Acids Res. 32: 141-110). The siRNA complex can be condensed into ananoparticle to allow efficient uptake of the siRNA through endocytosis.Also, the nucleic acid-condensing property of protamine has beencombined with specific antibodies to deliver siRNAs and can be used inthe invention (Song et al., 2005, Nat. Biotech. 23:709-717).

In order to treat an individual having T1D, to alleviate a sign orsymptom of the disease, RPS26 siRNA should be administered in aneffective dose, and can be sirected to SNP containing RPS26 sequences.The total treatment dose can be administered to a subject as a singledose or can be administered using a fractionated treatment protocol, inwhich multiple doses are administered over a more prolonged period oftime, for example, over the period of a day to allow administration of adaily dosage or over a longer period of time to administer a dose over adesired period of time. One skilled in the art would know that theamount of RPS26 siRNA required to obtain an effective dose in a subjectdepends on many factors, including the age, weight and general health ofthe subject, as well as the route of administration and the number oftreatments to be administered. In view of these factors, the skilledartisan would adjust the particular dose so as to obtain an effectivedose for treating an individual having T1D.

The effective dose of RPS26 siRNA will depend on the mode ofadministration, and the weight of the individual being treated. Thedosages described herein are generally those for an average adult butcan be adjusted for the treatment of children. The dose will generallyrange from about 0.001 mg to about 1000 mg.

The concentration of RPS26 siRNA in a particular formulation will dependon the mode and frequency of administration. A given daily dosage can beadministered in a single dose or in multiple doses so long as the RPS26siRNA concentration in the formulation results in the desired dailydosage. One skilled in the art can adjust the amount of RPS26 siRNA inthe formulation to allow administration of a single dose or in multipledoses that provide the desired concentration of RPS26 siRNA over a givenperiod of time.

In an individual suffering from T1D, in particular a more severe form ofthe disease, administration of RPS26 siRNA can be particularly usefulwhen administered in combination, for example, with a conventional agentfor treating such a disease. The skilled artisan would administer RPS26siRNA, alone or in combination and would monitor the effectiveness ofsuch treatment using routine methods such as pulmonary functiondetermination, radiologic, immunologic or, where indicated,histopathologic methods. Other conventional agents for the treatment ofdiabetes include insulin administration, glucagon administration oragents that alter levels of either of these two molecules. Glucophage®,Avandia®, Actos®, Januvia® and Glucovance® are examples of such agents.

Administration of the pharmaceutical preparation is preferably in an“effective amount” this being sufficient to show benefit to theindividual. This amount prevents, alleviates, abates, or otherwisereduces the severity of T1D symptoms in a patient.

The pharmaceutical preparation is formulated in dosage unit form forease of administration and uniformity of dosage. Dosage unit form, asused herein, refers to a physically discrete unit of the pharmaceuticalpreparation appropriate for the patient undergoing treatment. Eachdosage should contain a quantity of active ingredient calculated toproduce the desired effect in association with the selectedpharmaceutical carrier. Procedures for determining the appropriatedosage unit are well known to those skilled in the art.

Dosage units may be proportionately increased or decreased based on theweight of the patient. Appropriate concentrations for alleviation of aparticular pathological condition may be determined by dosageconcentration curve calculations, as known in the art.

As mentioned previously, a preferred embodiment of the inventioncomprises delivery of the SNP-containing RPS26 siRNA to a patient inneed thereof, and candidate siRNA compositions for use in the inventionare provided in Tables 5-10 (e.g., candidate siRNAs in Table 5=CDK2,Table 6=ERBB3, Table 7=IKZF4, Table 8=RAB5B, Table 9=RPS26, Table10=SUOX). The sequences suitable for use include several siRNA duplexes(i.e., sense and antisense sequences for a gene target region), as wellas several sequences of ‘sense’ strand alone. Those of skill in the artcan determine the sequence of an antisense siRNA strand based on thedisclosure of the sense strand, and will appreciate the differencebetween “U” and “T” designations in the sequences which correspond toRNA and DNA molecules, respectively.

The following examples are provided to illustrate certain embodiments ofthe invention. They are not intended to limit the invention in any way.

EXAMPLE I

550,000 single nucleotide polymorphisms (SNPs) were genotyped with theIllumina Human Hap550 Genotyping BeadChip¹¹ on the study population of563 T1D probands of European ancestry and 1,146 controls without T1D andwith matching ancestry (based on self report) plus 483 complete T1Dfamily trios of the same ancestry. Following this process, 16 trios, 2cases and 3 controls were removed due to genotyping yields <90%. Allpatients had clinically proven T1D.

In the case-control analysis, single-marker allele frequencies werecompared using χ² statistics for all markers while the transmissiondisequilibrium test (TDT) was used to calculate P-values of transmissiondistortion from heterozygous parents in affected parent-child trios. Theresulting P-values from the case-control and family-based analyses werethen combined using Fisher's method¹² to quantify the overall evidencefor association.

Association signals were further assessed to identify signals thatfulfilled the following criteria: (1) More than one SNP at a given locusexhibiting the same level of association in combined results from theStage 1 case-control (after EIGENSTRAT adjustment for populationstratification) and TDT analyses, with P<1×10⁻⁴; (2) the separateresults from the Stage 1 case-control association and TDT analyses hadto be P<0.05 each for more than one SNP at a given locus; (3) Oddsratios (OR) had to be in the same direction (more than one SNP at agiven locus) in both the TDT and combined results.

Overall, 62 SNPs at a total of 24 loci satisfying the above criteriawere selected (see Table 1). Following a replication attempt in theStage 2 cohort, three SNPs at locus 18 resulted in significantassociation (see Table 2), namely allele G of rs10876864, allele C ofrs1701704 and allele G of rs773107. These three SNPs reside onchromosome 12q13 in the vicinity of the following genes i.e. in a blockof linkage disequilibrium: RAS-associated protein (RAB5B), in whichrs773107 resides; Cyclin-dependent kinase 2 isoform 1 (CDK2); Sulfiteoxidase (SUOX); Zinc finger protein subfamily 1A4 (IKZF4); Ribosomalprotein S26 (RPS26); ErbB-3 isoform s precursor (ERBB3). As such,replicated association of T1D to a region on chromosome 12q13 harboringthe genes RAB5B, CDK2, SUOX, IKZF4, RPS26 and ERBB3 has been observed.

Standard convention for presenting the risk conferred by a given SNP isto describe the risk numerically for the less frequent allele in thepopulation i.e. the minor allele. On occasions, the minor allele is lessfrequent in the cases than in the controls and therefore yields a riskof less than 1 (i.e. it is termed “protective”). In this event, it isthe major, or more common, allele that confers risk. SNPs that showassociation are not necessarily causative themselves, rather they tagthe mutation which must reside on a nearby region (i.e. within a fewkilobases). The causative mutation itself may confer higher risk and berarer. Thus, the SNP association essentially indicates that there is acausative mutation nearby and that this SNP-containing gene is involvedin the pathogenesis of the disease and therefore can be utilized todetect susceptibility thereto. Many surrogate SNPs can be employed tocapture the same signal, and here they have been categorized into threeparts: CATEGORY 1: r2>0.9; CATEGORY 2: r2=0.8-0.9; CATEGORY 3:r2<0.8-0.7; see Table 3. Surrogates for these three SNPs have also beenidentified and are provided in Table 3 below.

Down regulation of RPS26 mRNA expression levels (or any of the genesmarked by the SNPs described herein, i.e., RAB5B, CDK2, SUOX, IKZF4,RPS26 and ERBB3) is desirable to inhibit production of the chromosome 12gene product. Reduction in the expression level of this protein shouldimpede or prevent the development of T1D. siRNA can be employed toregulate this locus, irrespective of the genetic status of theindividual. Accordingly, candidate siRNA molecules to be delivered topatients are listed in Tables 5-10. The genetic status is useful topredict who will develop the disease so it can be determined who willparticularly benefit from therapeutic intervention. Yet thoseindividuals who do not have this specific genetic predisposition of T1D,but have a family history of the disease or have another type of geneticpredisposition, could also benefit.

TABLE 1 Stage 1 candidate SNPs: Locus Chr No SNP Allele Case control PTDT OR TDT P Combined P Aff freq Ctrl frq OR 1 1 rs7543568 C 0.036 0.513.50 × 10⁻⁴ 2.00 × 10⁻⁴ 0.070 0.088 0.77 1 1 rs12094260 G 0.0058 0.490.0017 1.00 × 10⁻⁴ 0.049 0.067 0.72 1 2 rs2841578 A 1.50 × 10⁻³ 1.320.027 5.00 × 10⁻⁴ 0.159 0.132 1.25 1 2 rs1452619 G 1.53 × 10⁻³ 1.340.022 4.00 × 10⁻⁴ 0.160 0.132 1.25 2 3 rs6717144 T 9.82 × 10⁻⁴ 0.810.043 5.00 × 10⁻⁴ 0.274 0.305 0.86 2 3 rs7605368 A 2.66 × 10⁻³ 0.70 2.26× 10⁻³ 7.84 × 10⁻⁵ 0.194 0.226 0.83 2 3 rs12617390 G 1.86 × 10⁻³ 0.714.90 × 10⁻³ 1.00 × 10⁻⁴ 0.198 0.231 0.82 2 4 rs1348904 G 0.0043 1.299.38 × 10⁻³ 4.00 × 10⁻⁴ 0.373 0.331 1.21 2 4 rs12467601 C 0.0050 1.270.013 7.00 × 10⁻⁴ 0.374 0.333 1.20 3 5 rs2168422 A 6.99 × 10⁻³ 1.300.013 9.00 × 10⁻⁴ 0.293 0.252 1.24 3 5 rs7621973 C 1.70 × 10⁻² 1.36 4.67× 10⁻³ 8.00 × 10⁻⁴ 0.270 0.235 1.20 3 5 rs9310978 A 0.00362 1.26 0.0259.00 × 10⁻⁴ 0.308 0.277 1.16 3 6 rs694429 G 0.0017 1.34 0.015 3.00 ×10⁻⁴ 0.255 0.210 1.29 3 6 rs792829 G 4.94 × 10⁻² 1.38 1.60 × 10⁻³ 8.00 ×10⁻⁴ 0.369 0.336 1.15 3 7 rs333335 C 1.76 × 10⁻³ 1.27 0.011 2.00 × 10⁻⁴0.458 0.411 1.21 3 7 rs333318 T 6.35 × 10⁻³ 0.79 0.014 9.00 × 10⁻⁴ 0.4150.447 0.88 4 8 rs6856274 G 2.78 × 10⁻⁵ 1.26 0.040 1.62 × 10⁻⁵ 0.2440.203 1.27 4 8 rs1486993 A 2.26 × 10⁻⁵ 1.25 0.046 1.52 × 10⁻⁵ 0.2440.203 1.27 4 8 rs1486973 T 1.85 × 10⁻⁴ 1.28 0.029 6.94 × 10⁻⁵ 0.2270.190 1.25 4 8 rs4388143 A 1.28 × 10⁻³ 0.78 9.13 × 10⁻³ 1.00 × 10⁻⁴0.431 0.474 0.84 6 9 rs214506 C 0.019 1.43 2.14 × 10⁻⁴ 5.34 × 10⁻⁵ 0.4810.443 1.17 6 9 rs214566 G 0.0015 1.33 0.037 6.00 × 10⁻⁴ 0.173 0.131 1.396 9 rs214532 A 0.0029 1.32 0.013 4.00 × 10⁻⁴ 0.274 0.231 1.25 6 9rs445149 G 0.0060 1.33 0.012 8.00 × 10⁻⁴ 0.265 0.226 1.24 6 9 rs725550 G0.0078 0.66 8.50 × 10⁻⁴ 8.56 × 10⁻⁵ 0.178 0.218 0.78 6 10 rs1471540 T0.0011 1.32 0.025 3.00 × 10⁻⁴ 0.196 0.146 1.43 6 10 rs597544 T 0.00171.33 0.046 8.00 × 10⁻⁴ 0.150 0.109 1.44 6 11 rs9480754 G 0.0022 1.330.0060 2.00 × 10⁻⁴ 0.290 0.251 1.22 6 11 rs7773295 T 0.0026 1.28 0.0288.00 × 10⁻⁴ 0.225 0.184 1.28 7 12 rs10243170 G 0.0030 0.68 0.0046 2.00 ×10⁻⁴ 0.120 0.130 0.91 7 12 rs7778636 A 0.022 0.63 0.0039 9.00 × 10⁻⁴0.085 0.088 0.96 9 13 rs10758593 A 8.62 × 10⁻⁴ 1.22 0.037 4.00 × 10⁻⁴0.492 0.426 1.30 9 13 rs10758594 A 0.0014 1.21 0.041 6.00 × 10⁻⁴ 0.5130.451 1.28 9 14 rs824265 C 0.0092 0.61 0.0017 2.00 × 10⁻⁴ 0.104 0.1230.83 9 14 rs824241 A 0.0079 0.67 0.0061 5.00 × 10⁻⁴ 0.108 0.127 0.83 1015 rs4918487 T 0.0064 1.39 0.011 7.00 × 10⁻⁴ 0.202 0.153 1.40 10 15rs7917093 A 0.0079 1.39 0.011 9.00 × 10⁻⁴ 0.204 0.156 1.39 11 16rs4754458 A 0.0019 0.72 3.34 × 10⁻³ 8.14 × 10⁻⁵ 0.230 0.242 0.94 11 16rs12790005 C 2.47 × 10⁻³ 1.74 2.45 × 10⁻³ 7.88 × 10⁻⁵ 0.084 0.070 1.2111 16 rs11822881 A 0.0037 1.55 0.016 6.00 × 10⁻⁴ 0.080 0.067 1.21 11 16rs10488765 G 0.0092 1.63 6.35 × 10⁻³ 6.00 × 10⁻⁴ 0.079 0.069 1.15 12 17rs11048030 A 8.74 × 10⁻⁴ 1.59 0.010 1.00 × 10⁻⁴ 0.102 0.080 1.31 12 17rs7398236 C 0.0011 1.64 9.33 × 10⁻³ 1.00 × 10⁻⁴ 0.101 0.078 1.32 12 18rs2069408 G 5.12 × 10⁻³ 1.29 0.011 6.00 × 10⁻⁴ 0.357 0.305 1.27 12 18rs773107 G 3.20 × 10⁻⁵ 1.31 7.81 × 10⁻³ 4.05 × 10⁻⁶ 0.366 0.295 1.38 1218 rs10876864 G 2.07 × 10⁻⁴ 1.41 2.97 × 10⁻⁴ 1.08 × 10⁻⁶ 0.458 0.3881.34 12 18 rs1701704 C 2.46 × 10⁻⁵ 1.36 0.0016 7.16 × 10⁻⁷ 0.379 0.3031.40 12 18 rs705708 G 7.08 × 10⁻⁴ 1.22 0.028 2.00 × 10⁻⁴ 0.507 0.4611.21 15 19 rs1424695 A 3.34 × 10⁻³ 0.74 0.0021 8.94 × 10⁻⁵ 0.390 0.4220.88 15 19 rs1048048 T 2.31 × 10⁻⁴ 0.76 4.56 × 10⁻³ 1.55 × 10⁻⁵ 0.3000.335 0.85 16 20 rs151230 T 0.013 1.44 6.04 × 10⁻³ 8.00 × 10⁻⁴ 0.1610.139 1.19 16 20 rs9924471 T 0.0040 1.34 0.013 6.00 × 10⁻⁴ 0.208 0.1751.24 18 21 rs543347 T 1.37 × 10⁻³ 0.70 4.67 × 10⁻³ 8.27 × 10⁻⁵ 0.1110.147 0.72 18 21 rs540101 A 1.78 × 10⁻³ 0.71 6.43 × 10⁻³ 1.00 × 10⁻⁴0.111 0.147 0.72 19 22 rs602662 G 4.48 × 10⁻⁴ 0.74 1.82 × 10⁻³ 1.23 ×10⁻⁵ 0.450 0.491 0.85 19 22 rs485186 T 1.86 × 10⁻⁴ 0.75 2.31 × 10⁻³ 6.73× 10⁻⁶ 0.445 0.490 0.83 19 22 rs504963 C 5.09 × 10⁻⁴ 0.75 2.04 × 10⁻³1.54 × 10⁻⁵ 0.449 0.491 0.84 20 23 rs6076595 C 0.0019 0.79 0.032 7.00 ×10⁻⁴ 0.184 0.232 0.75 20 23 rs8119653 G 3.89 × 10⁻³ 0.78 0.013 5.00 ×10⁻⁴ 0.252 0.316 0.73 X 24 rs12854493 A 0.018 1.67 0.0039 8.00 × 10⁻⁴0.189 0.169 1.15 X 24 rs5907223 T 0.00142 1.41 0.039 6.00 × 10⁻⁴ 0.2380.191 1.32 X 24 rs7889974 G 5.55 × 10⁻⁴ 1.59 0.015 1.00 × 10⁻⁴ 0.1650.132 1.30

TABLE 2 Stage 2 results for locus 18 on chromosome 12q13. T:U TDT TDTCHR SNP TDT OR Chi-square TDT P 12 rs10876864 678:550 1.233 13.34 2.60 ×10⁻⁴ 12 rs1701704 635:506 1.255 14.58 1.34 × 10⁻⁴ 12 rs773107 609:4911.24 12.66 3.74 × 10⁻⁴

TABLE 3 All HapMap SNPs in the linkage disequilibrium block that haver2 > 0.5 in CEPH Utah Caucasians (CEU) to the three SNPs on 12q13(rs10876864, rs1701704 and rs773107). #pos1 pos2 pop marker1 marker2 D′r² 54660962 54655773 CEU rs773109 rs773107 1 0.959 54670954 54655773 CEUrs705698 rs773107 1 0.959 54676903 54655773 CEU rs705702 rs773107 10.959 54656178 54655773 CEU rs773108 rs773107 1 0.957 54721679 54655773CEU rs705704 rs773107 0.957 0.877 54689844 54655773 CEU rs772921rs773107 0.957 0.844 54698754 54655773 CEU rs1701704 rs773107 0.9570.844 54703195 54655773 CEU rs2456973 rs773107 0.957 0.843 5476844754655773 CEU rs2292239 rs773107 0.957 0.81 54766850 54655773 CEUrs877636 rs773107 0.954 0.801 54665327 54655773 CEU rs773114 rs773107 10.655 54665694 54655773 CEU rs1873914 rs773107 1 0.655 54687352 54655773CEU rs10876864 rs773107 0.951 0.615 54756892 54655773 CEU rs11171739rs773107 0.95 0.571 54763961 54655773 CEU rs2271194 rs773107 0.95 0.57154689844 54698754 CEU rs772921 rs1701704 1 1 54703195 54698754 CEUrs2456973 rs1701704 1 1 54721679 54698754 CEU rs705704 rs1701704 1 154768447 54698754 CEU rs2292239 rs1701704 0.959 0.884 54660962 54698754CEU rs773109 rs1701704 0.958 0.882 54676903 54698754 CEU rs705702rs1701704 0.958 0.882 54670954 54698754 CEU rs705698 rs1701704 0.9580.882 54766850 54698754 CEU rs877636 rs1701704 0.957 0.878 5465617854698754 CEU rs773108 rs1701704 0.956 0.876 54756892 54698754 CEUrs11171739 rs1701704 0.954 0.624 54763961 54698754 CEU rs2271194rs1701704 0.953 0.624 54665327 54698754 CEU rs773114 rs1701704 0.9080.587 54665694 54698754 CEU rs1873914 rs1701704 0.908 0.587 5479467654698754 CEU rs4759228 rs1701704 0.804 0.501 54665327 54687352 CEUrs773114 rs10876864 0.963 0.895 54665694 54687352 CEU rs1873914rs10876864 0.963 0.895 54756892 54687352 CEU rs11171739 rs10876864 0.9630.862 54763961 54687352 CEU rs2271194 rs10876864 0.963 0.862 5472167954687352 CEU rs705704 rs10876864 1 0.703 54656178 54687352 CEU rs773108rs10876864 0.952 0.681 54689844 54687352 CEU rs772921 rs10876864 0.9550.672 54698754 54687352 CEU rs1701704 rs10876864 0.955 0.672 5470319554687352 CEU rs2456973 rs10876864 0.954 0.669 54660962 54687352 CEUrs773109 rs10876864 0.953 0.643 54676903 54687352 CEU rs705702rs10876864 0.953 0.643 54670954 54687352 CEU rs705698 rs10876864 0.9530.643 54768447 54687352 CEU rs2292239 rs10876864 0.867 0.577 5476685054687352 CEU rs877636 rs10876864 0.861 0.562

EXAMPLE II

To determine if mRNA expression of any of the six genes at the 12q13locus were under regulatory influence of the SNPs that are present onthe HumanHap550 SNP chip and showing association with T1D, the “mRNA bySNP Browser” program was used to query the genes residing within the12q13 locus with respect to correlation with expression quantitativetrait loci (eQTLs). This program can be found on the world wide web at:(sph.umich.edu/csg/liang/asthma). A strong correlation was observedbetween the most significant T1D associated SNPs and eQTLs for the RPS26gene (see Table 4). None of the other five genes demonstrated eQTLsignals.

TABLE 4 eQTL correlation with two Affymetrix probes for the RPS26 geneand the most significant T1D associated SNPs at the 12q13 locus.Affymetrix Probe SNP ID Effect H2 LOD P-value 217753_s_at rs10876864−1.141 63.97 46.38 2.30 × 10⁻⁴⁸ 234885_at rs10876864 −0.57 15.98 11.652.40 × 10⁻¹³ 217753_s_at rs1701704 −1.024 47.75 33.04 5.80 × 10⁻³⁵234885_at rs1701704 −0.532 12.88 9.14 8.80 × 10⁻¹¹ 217753_s_at rs773107−0.941 39.77 27.88 9.20 × 10⁻³⁰ 234885_at rs773107 −0.474 10.06 7.247.70 × 10⁻⁹ 

These data show that the RPS26 gene is under strong regulatory influenceof the SNPs that associate with T1D at the 12q13 locus. While all sixgenes may contribute to development of T1D, these data suggest that theRPS26 gene may be most influential in the pathogenesis of T1D. Tables5-10 below contain candidate siRNA constructs directed to the genes atchromosome 12q13.

TABLE 5 Candidate siRNAs for CDK2, SEQ ID NOs: 12-251 are based onNM_052827 and SEQ ID NOs: 252-488 are based on NM_001798. SEQ ID NO: 12CCAGAGGCCCCGCCCCUGCtt SEQ ID NO: 13 GUUGCCGCCUCCCACCGAGtt SEQ ID NO: 14UGGCCAACUUGAAACAAUGtt SEQ ID NO: 15 UCUUGUCAAUUUGGCCAACtt SEQ ID NO: 16ACCUCUCGCUCUUGUCAAUtt SEQ ID NO: 17 CGCAGUAUACCUCUCGCUCtt SEQ ID NO: 18CUUUUCCACCUUUUGGAAGtt SEQ ID NO: 19 CUCCGAUCUUUUCCACCUUtt SEQ ID NO: 20CUCUCCGAUCUUUUCCACCtt SEQ ID NO: 21 ACGUGCCCUCUCCGAUCUUtt SEQ ID NO: 22GUACGUGCCCUCUCCGAUCtt SEQ ID NO: 23 CGUCAACUUGUUUCUGGCUtt SEQ ID NO: 24ACCUCUCCCGUCAACUUGUtt SEQ ID NO: 25 CACCACCUCUCCCGUCAACtt SEQ ID NO: 26AGUGUCCAGGCGGAUUUUCtt SEQ ID NO: 27 CUCAGUGUCCAGGCGGAUUtt SEQ ID NO: 28GUCUCAGUGUCCAGGCGGAtt SEQ ID NO: 29 AUUAGGAUGGUUAAGCUCCtt SEQ ID NO: 30CUUGACAAUAUUAGGAUGGtt SEQ ID NO: 31 AUCCAGCAGCUUGACAAUAtt SEQ ID NO: 32GUGAAUGACAUCCAGCAGCtt SEQ ID NO: 33 AAACCAGGUAGAGUUUAUUtt SEQ ID NO: 34AAAAACCAGGUAGAGUUUAtt SEQ ID NO: 35 UUCAAAAACCAGGUAGAGUtt SEQ ID NO: 36UGAGAUCUUGGUGCAGAAAtt SEQ ID NO: 37 CCAUGAAUUUCUUGAGAUCtt SEQ ID NO: 38AGAGGCAUCCAUGAAUUUCtt SEQ ID NO: 39 AGCAGAGGCAUCCAUGAAUtt SEQ ID NO: 40CAGCUGGAACAGAUAGCUCtt SEQ ID NO: 41 AAUAAGCAGAUUCUGAGGUtt SEQ ID NO: 42CUCUGUGUUAAUAAGCAGAtt SEQ ID NO: 43 CUUGAUGGCCCCCUCUGUGtt SEQ ID NO: 44UAGUCCAAAGUCUGCUAGCtt SEQ ID NO: 45 CCACUUGGGGAAACUUGGCtt SEQ ID NO: 46CGGGCCCACUUGGGGAAACtt SEQ ID NO: 47 AAAAUCUUGCCGGGCCCACtt SEQ ID NO: 48GUACAACUUUACUAAAAUCtt SEQ ID NO: 49 AUCCAGGGGAGGUACAACUtt SEQ ID NO: 50AUAACAAGCUCCGUCCAUCtt SEQ ID NO: 51 UAGGGUCGUAGUGCAGCAUtt SEQ ID NO: 52CUUGGCCGAAAUCCGCUUGtt SEQ ID NO: 53 UGCCUUGGCCGAAAUCCGCtt SEQ ID NO: 54AGGGUGAGCCAGGGCUGCCtt SEQ ID NO: 55 UCGAAGAUGGGGUACUGGCtt SEQ ID NO: 56UGAGAUUAGGGCUGGGGGCtt SEQ ID NO: 57 ACUGGAGGAGAGGGUGAGAtt SEQ ID NO: 58GGUGAGUGUUUAAGGCAAGtt SEQ ID NO: 59 AAGACUAGAAGGUGAGUGUtt SEQ ID NO: 60CACCCCUGUAUUCCCAGAGtt SEQ ID NO: 61 CCCCCCUUUCACCCCUGUAtt SEQ ID NO: 62UUUUCACUGGUUCCCCCCUtt SEQ ID NO: 63 UUCCUUUCAUUUUCACUGGtt SEQ ID NO: 64ACUGAAACUUCCUUUCAUUtt SEQ ID NO: 65 AUACUGAAACUUCCUUUCAtt SEQ ID NO: 66UCUAAUACUGAAACUUCCUtt SEQ ID NO: 67 GUGCAUCUAAUACUGAAACtt SEQ ID NO: 68AAGGGUGGUGGAGGCUAACtt SEQ ID NO: 69 UAUUUUUAUACCAACCCUCtt SEQ ID NO: 70GGCUUUUUUAAAAUUAUUUtt SEQ ID NO: 71 AAGGCUUUUUUAAAAUUAUtt SEQ ID NO: 72UAGGAAGGCUUUUUUAAAAtt SEQ ID NO: 73 AACGUGUAGGAAGGCUUUUtt SEQ ID NO: 74CUAACGUGUAGGAAGGCUUtt SEQ ID NO: 75 AUCUAACGUGUAGGAAGGCtt SEQ ID NO: 76AUUAUGGGGCAUUCAGAGAtt SEQ ID NO: 77 AAAUAAUAAUUAUGGGGCAtt SEQ ID NO: 78CAAACACUGGAAAUAAUAAtt SEQ ID NO: 79 CAUUGUGGCAGCAGGAGGCtt SEQ ID NO: 80CAUUUGGCCUUUAUAAACAtt SEQ ID NO: 81 CCCCGCUAUCAUUUGGCCUtt SEQ ID NO: 82ACUUAGCCCCCGCUAUCAUtt SEQ ID NO: 83 GGUUCUCAAAAGCACCAACtt SEQ ID NO: 84GUGGUUUUGUUUUACUUGGtt SEQ ID NO: 85 CCCAGUGGUUUUGUUUUACtt SEQ ID NO: 86UCCUCCCAGUGGUUUUGUUtt SEQ ID NO: 87 ACUCCUCCCAGUGGUUUUGtt SEQ ID NO: 88UAGACUCCUCCCAGUGGUUtt SEQ ID NO: 89 AAUAGACUCCUCCCAGUGGtt SEQ ID NO: 90AUUUUUUCAACCGAAUUCUtt SEQ ID NO: 91 AUCUAUUUUUUCAACCGAAtt SEQ ID NO: 92AACUGAUUGGAUCUAUUUUtt SEQ ID NO: 93 UAAACUGAUUGGAUCUAUUtt SEQ ID NO: 94UAUAAACUGAUUGGAUCUAtt SEQ ID NO: 95 UAACUAGGGUAUAAACUGAtt SEQ ID NO: 96UCUUCAGUCUCCCAGCCUAtt SEQ ID NO: 97 GCCCCACCCGGGCUGAGUCtt SEQ ID NO: 98GGACUGGGGCCAAUCAUUUtt SEQ ID NO: 99 GGGGACUGGGGCCAAUCAUtt SEQ ID NO: 100UGUCUCAGGGCCUCCCAGAtt SEQ ID NO: 101 GCCAUGGUGAAGCAAUAGAtt SEQ ID NO:102 ACUAAAAGGAAGAGAAAAAtt SEQ ID NO: 103 AAAAUGGGAUCAGGGAUCCtt SEQ IDNO: 104 AUGAUGCCUAAACCCUAACtt SEQ ID NO: 105 CCCUGAAAAAGUGUCAGCAtt SEQID NO: 106 UUCUUUUAAAGAAAUAUUUtt SEQ ID NO: 107 CCUUCUUUUAAAGAAAUAUttSEQ ID NO: 108 AUAAUUGUUCAUCCUUCUUtt SEQ ID NO: 109AUAUAAUUGUUCAUCCUUCtt SEQ ID NO: 110 UAAAUAUAAUUGUUCAUCCtt SEQ ID NO:111 UGAAAUAUAAAUAUAAUUGtt SEQ ID NO: 112 ACCUGAAAUAUAAAUAUAAtt SEQ IDNO: 113 AAAAAAGCCAACUCUACUAtt SEQ ID NO: 114 UUUUUUUUUAGCACUGUCAtt SEQID NO: 115 AAAAAAAUGCUUUUUUUUUtt SEQ ID NO: 116 AAAAAAAAAUGCUUUUUUUttSEQ ID NO: 117 UAAAAAAAAAAUGCUUUUUtt SEQ ID NO: 118CAUAAAAAAAAAAUGCUUUtt SEQ ID NO: 119 AUCAUAAAAAAAAAAUGCUtt SEQ ID NO:120 AACUAAAUUACAAAUAACGtt SEQ ID NO: 121 UAAUGAGCUACAAACUAAAtt SEQ IDNO: 122 UAAAACUAGGCACAUUUUUtt SEQ ID NO: 123 UAUAAAACUAGGCACAUUUtt SEQID NO: 124 UUUAUAAAACUAGGCACAUtt SEQ ID NO: 125 UUGUUUUUUUUUUUUUUUUttSEQ ID NO: 126 UUUUGUUUUUUUUUUUUUUtt SEQ ID NO: 127UUUUUUGUUUUUUUUUUUUtt SEQ ID NO: 128 UUUUUUUUGUUUUUUUUUUtt SEQ ID NO:129 UUUUUUUUUUGUUUUUUUUtt SEQ ID NO: 130 UUUUUUUUUUUUGUUUUUUtt SEQ IDNO: 131 UUUUUUUUUUUUUUGUUUUtt SEQ ID NO: 132 GCAGGGGCGGGGCCUCUGGtt SEQID NO: 133 CUCGGUGGGAGGCGGCAACtt SEQ ID NO: 134 CAUUGUUUCAAGUUGGCCAttSEQ ID NO: 135 GUUGGCCAAAUUGACAAGAtt SEQ ID NO: 136AUUGACAAGAGCGAGAGGUtt SEQ ID NO: 137 GAGCGAGAGGUAUACUGCGtt SEQ ID NO:138 CUUCCAAAAGGUGGAAAAGtt SEQ ID NO: 139 AAGGUGGAAAAGAUCGGAGtt SEQ IDNO: 140 GGUGGAAAAGAUCGGAGAGtt SEQ ID NO: 141 AAGAUCGGAGAGGGCACGUtt SEQID NO: 142 GAUCGGAGAGGGCACGUACtt SEQ ID NO: 143 AGCCAGAAACAAGUUGACGttSEQ ID NO: 144 ACAAGUUGACGGGAGAGGUtt SEQ ID NO: 145GUUGACGGGAGAGGUGGUGtt SEQ ID NO: 146 GAAAAUCCGCCUGGACACUtt SEQ ID NO:147 AAUCCGCCUGGACACUGAGtt SEQ ID NO: 148 UCCGCCUGGACACUGAGACtt SEQ IDNO: 149 GGAGCUUAACCAUCCUAAUtt SEQ ID NO: 150 CCAUCCUAAUAUUGUCAAGtt SEQID NO: 151 UAUUGUCAAGCUGCUGGAUtt SEQ ID NO: 152 GCUGCUGGAUGUCAUUCACttSEQ ID NO: 153 AAUAAACUCUACCUGGUUUtt SEQ ID NO: 154UAAACUCUACCUGGUUUUUtt SEQ ID NO: 155 ACUCUACCUGGUUUUUGAAtt SEQ ID NO:156 UUUCUGCACCAAGAUCUCAtt SEQ ID NO: 157 GAUCUCAAGAAAUUCAUGGtt SEQ IDNO: 158 GAAAUUCAUGGAUGCCUCUtt SEQ ID NO: 159 AUUCAUGGAUGCCUCUGCUtt SEQID NO: 160 GAGCUAUCUGUUCCAGCUGtt SEQ ID NO: 161 ACCUCAGAAUCUGCUUAUUttSEQ ID NO: 162 UCUGCUUAUUAACACAGAGtt SEQ ID NO: 163CACAGAGGGGGCCAUCAAGtt SEQ ID NO: 164 GCUAGCAGACUUUGGACUAtt SEQ ID NO:165 GCCAAGUUUCCCCAAGUGGtt SEQ ID NO: 166 GUUUCCCCAAGUGGGCCCGtt SEQ IDNO: 167 GUGGGCCCGGCAAGAUUUUtt SEQ ID NO: 168 GAUUUUAGUAAAGUUGUACtt SEQID NO: 169 AGUUGUACCUCCCCUGGAUtt SEQ ID NO: 170 GAUGGACGGAGCUUGUUAUttSEQ ID NO: 171 AUGCUGCACUACGACCCUAtt SEQ ID NO: 172CAAGCGGAUUUCGGCCAAGtt SEQ ID NO: 173 GCGGAUUUCGGCCAAGGCAtt SEQ ID NO:174 GGCAGCCCUGGCUCACCCUtt SEQ ID NO: 175 GCCAGUACCCCAUCUUCGAtt SEQ IDNO: 176 GCCCCCAGCCCUAAUCUCAtt SEQ ID NO: 177 UCUCACCCUCUCCUCCAGUtt SEQID NO: 178 CUUGCCUUAAACACUCACCtt SEQ ID NO: 179 ACACUCACCUUCUAGUCUUttSEQ ID NO: 180 CUCUGGGAAUACAGGGGUGtt SEQ ID NO: 181UACAGGGGUGAAAGGGGGGtt SEQ ID NO: 182 AGGGGGGAACCAGUGAAAAtt SEQ ID NO:183 CCAGUGAAAAUGAAAGGAAtt SEQ ID NO: 184 AAUGAAAGGAAGUUUCAGUtt SEQ IDNO: 185 UGAAAGGAAGUUUCAGUAUtt SEQ ID NO: 186 AGGAAGUUUCAGUAUUAGAtt SEQID NO: 187 GUUUCAGUAUUAGAUGCACtt SEQ ID NO: 188 GUUAGCCUCCACCACCCUUttSEQ ID NO: 189 GAGGGUUGGUAUAAAAAUAtt SEQ ID NO: 190AAAUAAUUUUAAAAAAGCCtt SEQ ID NO: 191 AUAAUUUUAAAAAAGCCUUtt SEQ ID NO:192 UUUUAAAAAAGCCUUCCUAtt SEQ ID NO: 193 AAAAGCCUUCCUACACGUUtt SEQ IDNO: 194 AAGCCUUCCUACACGUUAGtt SEQ ID NO: 195 GCCUUCCUACACGUUAGAUtt SEQID NO: 196 UCUCUGAAUGCCCCAUAAUtt SEQ ID NO: 197 UGCCCCAUAAUUAUUAUUUttSEQ ID NO: 198 UUAUUAUUUCCAGUGUUUGtt SEQ ID NO: 199GCCUCCUGCUGCCACAAUGtt SEQ ID NO: 200 UGUUUAUAAAGGCCAAAUGtt SEQ ID NO:201 AGGCCAAAUGAUAGCGGGGtt SEQ ID NO: 202 AUGAUAGCGGGGGCUAAGUtt SEQ IDNO: 203 GUUGGUGCUUUUGAGAACCtt SEQ ID NO: 204 CCAAGUAAAACAAAACCACtt SEQID NO: 205 GUAAAACAAAACCACUGGGtt SEQ ID NO: 206 AACAAAACCACUGGGAGGAttSEQ ID NO: 207 CAAAACCACUGGGAGGAGUtt SEQ ID NO: 208AACCACUGGGAGGAGUCUAtt SEQ ID NO: 209 CCACUGGGAGGAGUCUAUUtt SEQ ID NO:210 AGAAUUCGGUUGAAAAAAUtt SEQ ID NO: 211 UUCGGUUGAAAAAAUAGAUtt SEQ IDNO: 212 AAAAUAGAUCCAAUCAGUUtt SEQ ID NO: 213 AAUAGAUCCAAUCAGUUUAtt SEQID NO: 214 UAGAUCCAAUCAGUUUAUAtt SEQ ID NO: 215 UCAGUUUAUACCCUAGUUAttSEQ ID NO: 216 UAGGCUGGGAGACUGAAGAtt SEQ ID NO: 217GACUCAGCCCGGGUGGGGCtt SEQ ID NO: 218 AAAUGAUUGGCCCCAGUCCtt SEQ ID NO:219 AUGAUUGGCCCCAGUCCCCtt SEQ ID NO: 220 UCUGGGAGGCCCUGAGACAtt SEQ IDNO: 221 UCUAUUGCUUCACCAUGGCtt SEQ ID NO: 222 UUUUUCUCUUCCUUUUAGUtt SEQID NO: 223 GGAUCCCUGAUCCCAUUUUtt SEQ ID NO: 224 GUUAGGGUUUAGGCAUCAUttSEQ ID NO: 225 UGCUGACACUUUUUCAGGGtt SEQ ID NO: 226AAAUAUUUCUUUAAAAGAAtt SEQ ID NO: 227 AUAUUUCUUUAAAAGAAGGtt SEQ ID NO:228 AAGAAGGAUGAACAAUUAUtt SEQ ID NO: 229 GAAGGAUGAACAAUUAUAUtt SEQ IDNO: 230 GGAUGAACAAUUAUAUUUAtt SEQ ID NO: 231 CAAUUAUAUUUAUAUUUCAtt SEQID NO: 232 UUAUAUUUAUAUUUCAGGUtt SEQ ID NO: 233 UAGUAGAGUUGGCUUUUUUttSEQ ID NO: 234 UGACAGUGCUAAAAAAAAAtt SEQ ID NO: 235AAAAAAAAAGCAUUUUUUUtt SEQ ID NO: 236 AAAAAAAGCAUUUUUUUUUtt SEQ ID NO:237 AAAAAGCAUUUUUUUUUUAtt SEQ ID NO: 238 AAAGCAUUUUUUUUUUAUGtt SEQ IDNO: 239 AGCAUUUUUUUUUUAUGAUtt SEQ ID NO: 240 CGUUAUUUGUAAUUUAGUUtt SEQID NO: 241 UUUAGUUUGUAGCUCAUUAtt SEQ ID NO: 242 AAAAAUGUGCCUAGUUUUAttSEQ ID NO: 243 AAAUGUGCCUAGUUUUAUAtt SEQ ID NO: 244AUGUGCCUAGUUUUAUAAAtt SEQ ID NO: 245 AAAAAAAAAAAAAAAACAAtt SEQ ID NO:246 AAAAAAAAAAAAAACAAAAtt SEQ ID NO: 247 AAAAAAAAAAAACAAAAAAtt SEQ IDNO: 248 AAAAAAAAAACAAAAAAAAtt SEQ ID NO: 249 AAAAAAAACAAAAAAAAAAtt SEQID NO: 250 AAAAAACAAAAAAAAAAAAtt SEQ ID NO: 251 AAAACAAAAAAAAAAAAAAttSEQ ID NO: 252 CCAGAGGCCCCGCCCCUGCtt SEQ ID NO: 253GUUGCCGCCUCCCACCGAGtt SEQ ID NO: 254 UGGCCAACUUGAAACAAUGtt SEQ ID NO:255 UCUUGUCAAUUUGGCCAACtt SEQ ID NO: 256 ACCUCUCGCUCUUGUCAAUtt SEQ IDNO: 257 CGCAGUAUACCUCUCGCUCtt SEQ ID NO: 258 CUUUUCCACCUUUUGGAAGtt SEQID NO: 259 CUCCGAUCUUUUCCACCUUtt SEQ ID NO: 260 CUCUCCGAUCUUUUCCACCttSEQ ID NO: 261 ACGUGCCCUCUCCGAUCUUtt SEQ ID NO: 262GUACGUGCCCUCUCCGAUCtt SEQ ID NO: 263 CGUCAACUUGUUUCUGGCUtt SEQ ID NO:264 ACCUCUCCCGUCAACUUGUtt SEQ ID NO: 265 CACCACCUCUCCCGUCAACtt SEQ IDNO: 266 AGUGUCCAGGCGGAUUUUCtt SEQ ID NO: 267 CUCAGUGUCCAGGCGGAUUtt SEQID NO: 268 GUCUCAGUGUCCAGGCGGAtt SEQ ID NO: 269 AUUAGGAUGGUUAAGCUCCttSEQ ID NO: 270 CUUGACAAUAUUAGGAUGGtt SEQ ID NO: 271AUCCAGCAGCUUGACAAUAtt SEQ ID NO: 272 GUGAAUGACAUCCAGCAGCtt SEQ ID NO:273 AAACCAGGUAGAGUUUAUUtt SEQ ID NO: 274 AAAAACCAGGUAGAGUUUAtt SEQ IDNO: 275 UUCAAAAACCAGGUAGAGUtt SEQ ID NO: 276 UGAGAUCUUGGUGCAGAAAtt SEQID NO: 277 CCAUGAAUUUCUUGAGAUCtt SEQ ID NO: 278 AGAGGCAUCCAUGAAUUUCttSEQ ID NO: 279 AGCAGAGGCAUCCAUGAAUtt SEQ ID NO: 280CAGCUGGAACAGAUAGCUCtt SEQ ID NO: 281 AAUAAGCAGAUUCUGAGGUtt SEQ ID NO:282 CUCUGUGUUAAUAAGCAGAtt SEQ ID NO: 283 CUUGAUGGCCCCCUCUGUGtt SEQ IDNO: 284 UAGUCCAAAGUCUGCUAGCtt SEQ ID NO: 285 AUUUGCAGCCCAGGAGGAUtt SEQID NO: 286 CACAGCUGUGGAAUAAUAUtt SEQ ID NO: 287 CCACUUGGGGAAACUUGGCttSEQ ID NO: 288 CGGGCCCACUUGGGGAAACtt SEQ ID NO: 289AAAAUCUUGCCGGGCCCACtt SEQ ID NO: 290 GUACAACUUUACUAAAAUCtt SEQ ID NO:291 AUCCAGGGGAGGUACAACUtt SEQ ID NO: 292 AUAACAAGCUCCGUCCAUCtt SEQ IDNO: 293 UAGGGUCGUAGUGCAGCAUtt SEQ ID NO: 294 CUUGGCCGAAAUCCGCUUGtt SEQID NO: 295 UGCCUUGGCCGAAAUCCGCtt SEQ ID NO: 296 AGGGUGAGCCAGGGCUGCCttSEQ ID NO: 297 UCGAAGAUGGGGUACUGGCtt SEQ ID NO: 298UGAGAUUAGGGCUGGGGGCtt SEQ ID NO: 299 ACUGGAGGAGAGGGUGAGAtt SEQ ID NO:300 GGUGAGUGUUUAAGGCAAGtt SEQ ID NO: 301 AAGACUAGAAGGUGAGUGUtt SEQ IDNO: 302 CACCCCUGUAUUCCCAGAGtt SEQ ID NO: 303 CCCCCCUUUCACCCCUGUAtt SEQID NO: 304 UUUUCACUGGUUCCCCCCUtt SEQ ID NO: 305 UUCCUUUCAUUUUCACUGGttSEQ ID NO: 306 ACUGAAACUUCCUUUCAUUtt SEQ ID NO: 307AUACUGAAACUUCCUUUCAtt SEQ ID NO: 308 UCUAAUACUGAAACUUCCUtt SEQ ID NO:309 GUGCAUCUAAUACUGAAACtt SEQ ID NO: 310 AAGGGUGGUGGAGGCUAACtt SEQ IDNO: 311 UAUUUUUAUACCAACCCUCtt SEQ ID NO: 312 GGCUUUUUUAAAAUUAUUUtt SEQID NO: 313 AAGGCUUUUUUAAAAUUAUtt SEQ ID NO: 314 UAGGAAGGCUUUUUUAAAAttSEQ ID NO: 315 AACGUGUAGGAAGGCUUUUtt SEQ ID NO: 316CUAACGUGUAGGAAGGCUUtt SEQ ID NO: 317 AUCUAACGUGUAGGAAGGCtt SEQ ID NO:318 AUUAUGGGGCAUUCAGAGAtt SEQ ID NO: 319 AAAUAAUAAUUAUGGGGCAtt SEQ IDNO: 320 CAAACACUGGAAAUAAUAAtt SEQ ID NO: 321 CAUUGUGGCAGCAGGAGGCtt SEQID NO: 322 CAUUUGGCCUUUAUAAACAtt SEQ ID NO: 323 CCCCGCUAUCAUUUGGCCUttSEQ ID NO: 324 ACUUAGCCCCCGCUAUCAUtt SEQ ID NO: 325GGUUCUCAAAAGCACCAACtt SEQ ID NO: 326 GUGGUUUUGUUUUACUUGGtt SEQ ID NO:327 CCCAGUGGUUUUGUUUUACtt SEQ ID NO: 328 UCCUCCCAGUGGUUUUGUUtt SEQ IDNO: 329 ACUCCUCCCAGUGGUUUUGtt SEQ ID NO: 330 UAGACUCCUCCCAGUGGUUtt SEQID NO: 331 AAUAGACUCCUCCCAGUGGtt SEQ ID NO: 332 AUUUUUUCAACCGAAUUCUttSEQ ID NO: 333 AUCUAUUUUUUCAACCGAAtt SEQ ID NO: 334AACUGAUUGGAUCUAUUUUtt SEQ ID NO: 335 UAAACUGAUUGGAUCUAUUtt SEQ ID NO:336 UAUAAACUGAUUGGAUCUAtt SEQ ID NO: 337 UAACUAGGGUAUAAACUGAtt SEQ IDNO: 338 UCUUCAGUCUCCCAGCCUAtt SEQ ID NO: 339 GCCCCACCCGGGCUGAGUCtt SEQID NO: 340 GGACUGGGGCCAAUCAUUUtt SEQ ID NO: 341 GGGGACUGGGGCCAAUCAUttSEQ ID NO: 342 UGUCUCAGGGCCUCCCAGAtt SEQ ID NO: 343GCCAUGGUGAAGCAAUAGAtt SEQ ID NO: 344 ACUAAAAGGAAGAGAAAAAtt SEQ ID NO:345 AAAAUGGGAUCAGGGAUCCtt SEQ ID NO: 346 AUGAUGCCUAAACCCUAACtt SEQ IDNO: 347 CCCUGAAAAAGUGUCAGCAtt SEQ ID NO: 348 UUCUUUUAAAGAAAUAUUUtt SEQID NO: 349 CCUUCUUUUAAAGAAAUAUtt SEQ ID NO: 350 AUAAUUGUUCAUCCUUCUUttSEQ ID NO: 351 AUAUAAUUGUUCAUCCUUCtt SEQ ID NO: 352UAAAUAUAAUUGUUCAUCCtt SEQ ID NO: 353 UGAAAUAUAAAUAUAAUUGtt SEQ ID NO:354 ACCUGAAAUAUAAAUAUAAtt SEQ ID NO: 355 AAAAAAGCCAACUCUACUAtt SEQ IDNO: 356 UUUUUUUUUAGCACUGUCAtt SEQ ID NO: 357 AAAAAAAUGCUUUUUUUUUtt SEQID NO: 358 AAAAAAAAAUGCUUUUUUUtt SEQ ID NO: 359 UAAAAAAAAAAUGCUUUUUttSEQ ID NO: 360 CAUAAAAAAAAAAUGCUUUtt SEQ ID NO: 361AUCAUAAAAAAAAAAUGCUtt SEQ ID NO: 362 AACUAAAUUACAAAUAACGtt SEQ ID NO:363 UAAUGAGCUACAAACUAAAtt SEQ ID NO: 364 UAAAACUAGGCACAUUUUUtt SEQ IDNO: 365 UAUAAAACUAGGCACAUUUtt SEQ ID NO: 366 UUUAUAAAACUAGGCACAUtt SEQID NO: 367 UUGUUUUUUUUUUUUUUUUtt SEQ ID NO: 368 UUUUGUUUUUUUUUUUUUUttSEQ ID NO: 369 UUUUUUGUUUUUUUUUUUUtt SEQ ID NO: 370UUUUUUUUGUUUUUUUUUUtt SEQ ID NO: 371 UUUUUUUUUUGUUUUUUUUtt SEQ ID NO:372 UUUUUUUUUUUUGUUUUUUtt SEQ ID NO: 373 UUUUUUUUUUUUUUGUUUUtt SEQ IDNO: 374 GCAGGGGCGGGGCCUCUGGtt SEQ ID NO: 375 CUCGGUGGGAGGCGGCAACtt SEQID NO: 376 CAUUGUUUCAAGUUGGCCAtt SEQ ID NO: 377 GUUGGCCAAAUUGACAAGAttSEQ ID NO: 378 AUUGACAAGAGCGAGAGGUtt SEQ ID NO: 379GAGCGAGAGGUAUACUGCGtt SEQ ID NO: 380 CUUCCAAAAGGUGGAAAAGtt SEQ ID NO:381 AAGGUGGAAAAGAUCGGAGtt SEQ ID NO: 382 GGUGGAAAAGAUCGGAGAGtt SEQ IDNO: 383 AAGAUCGGAGAGGGCACGUtt SEQ ID NO: 384 GAUCGGAGAGGGCACGUACtt SEQID NO: 385 AGCCAGAAACAAGUUGACGtt SEQ ID NO: 386 ACAAGUUGACGGGAGAGGUttSEQ ID NO: 387 GUUGACGGGAGAGGUGGUGtt SEQ ID NO: 388GAAAAUCCGCCUGGACACUtt SEQ ID NO: 389 AAUCCGCCUGGACACUGAGtt SEQ ID NO:390 UCCGCCUGGACACUGAGACtt SEQ ID NO: 391 GGAGCUUAACCAUCCUAAUtt SEQ IDNO: 392 CCAUCCUAAUAUUGUCAAGtt SEQ ID NO: 393 UAUUGUCAAGCUGCUGGAUtt SEQID NO: 394 GCUGCUGGAUGUCAUUCACtt SEQ ID NO: 395 AAUAAACUCUACCUGGUUUttSEQ ID NO: 396 UAAACUCUACCUGGUUUUUtt SEQ ID NO: 397ACUCUACCUGGUUUUUGAAtt SEQ ID NO: 398 UUUCUGCACCAAGAUCUCAtt SEQ ID NO:399 GAUCUCAAGAAAUUCAUGGtt SEQ ID NO: 400 GAAAUUCAUGGAUGCCUCUtt SEQ IDNO: 401 AUUCAUGGAUGCCUCUGCUtt SEQ ID NO: 402 GAGCUAUCUGUUCCAGCUGtt SEQID NO: 403 ACCUCAGAAUCUGCUUAUUtt SEQ ID NO: 404 UCUGCUUAUUAACACAGAGttSEQ ID NO: 405 CACAGAGGGGGCCAUCAAGtt SEQ ID NO: 406GCUAGCAGACUUUGGACUAtt SEQ ID NO: 407 AUCCUCCUGGGCUGCAAAUtt SEQ ID NO:408 AUAUUAUUCCACAGCUGUGtt SEQ ID NO: 409 GCCAAGUUUCCCCAAGUGGtt SEQ IDNO: 410 GUUUCCCCAAGUGGGCCCGtt SEQ ID NO: 411 GUGGGCCCGGCAAGAUUUUtt SEQID NO: 412 GAUUUUAGUAAAGUUGUACtt SEQ ID NO: 413 AGUUGUACCUCCCCUGGAUttSEQ ID NO: 414 GAUGGACGGAGCUUGUUAUtt SEQ ID NO: 415AUGCUGCACUACGACCCUAtt SEQ ID NO: 416 CAAGCGGAUUUCGGCCAAGtt SEQ ID NO:417 GCGGAUUUCGGCCAAGGCAtt SEQ ID NO: 418 GGCAGCCCUGGCUCACCCUtt SEQ IDNO: 419 GCCAGUACCCCAUCUUCGAtt SEQ ID NO: 420 GCCCCCAGCCCUAAUCUCAtt SEQID NO: 421 UCUCACCCUCUCCUCCAGUtt SEQ ID NO: 422 CUUGCCUUAAACACUCACCttSEQ ID NO: 423 ACACUCACCUUCUAGUCUUtt SEQ ID NO: 424CUCUGGGAAUACAGGGGUGtt SEQ ID NO: 425 UACAGGGGUGAAAGGGGGGtt SEQ ID NO:426 AGGGGGGAACCAGUGAAAAtt SEQ ID NO: 427 CCAGUGAAAAUGAAAGGAAtt SEQ IDNO: 428 AAUGAAAGGAAGUUUCAGUtt SEQ ID NO: 429 UGAAAGGAAGUUUCAGUAUtt SEQID NO: 430 AGGAAGUUUCAGUAUUAGAtt SEQ ID NO: 431 GUUUCAGUAUUAGAUGCACttSEQ ID NO: 432 GUUAGCCUCCACCACCCUUtt SEQ ID NO: 433GAGGGUUGGUAUAAAAAUAtt SEQ ID NO: 434 AAAUAAUUUUAAAAAAGCCtt SEQ ID NO:435 AUAAUUUUAAAAAAGCCUUtt SEQ ID NO: 436 UUUUAAAAAAGCCUUCCUAtt SEQ IDNO: 437 AAAAGCCUUCCUACACGUUtt SEQ ID NO: 438 AAGCCUUCCUACACGUUAGtt SEQID NO: 439 GCCUUCCUACACGUUAGAUtt SEQ ID NO: 440 UCUCUGAAUGCCCCAUAAUttSEQ ID NO: 441 UGCCCCAUAAUUAUUAUUUtt SEQ ID NO: 442UUAUUAUUUCCAGUGUUUGtt SEQ ID NO: 443 GCCUCCUGCUGCCACAAUGtt SEQ ID NO:444 UGUUUAUAAAGGCCAAAUGtt SEQ ID NO: 445 AGGCCAAAUGAUAGCGGGGtt SEQ IDNO: 446 AUGAUAGCGGGGGCUAAGUtt SEQ ID NO: 447 GUUGGUGCUUUUGAGAACCtt SEQID NO: 448 CCAAGUAAAACAAAACCACtt SEQ ID NO: 449 GUAAAACAAAACCACUGGGttSEQ ID NO: 450 AACAAAACCACUGGGAGGAtt SEQ ID NO: 451CAAAACCACUGGGAGGAGUtt SEQ ID NO: 452 AACCACUGGGAGGAGUCUAtt SEQ ID NO:453 CCACUGGGAGGAGUCUAUUtt SEQ ID NO: 454 AGAAUUCGGUUGAAAAAAUtt SEQ IDNO: 455 UUCGGUUGAAAAAAUAGAUtt SEQ ID NO: 456 AAAAUAGAUCCAAUCAGUUtt SEQID NO: 457 AAUAGAUCCAAUCAGUUUAtt SEQ ID NO: 458 UAGAUCCAAUCAGUUUAUAttSEQ ID NO: 459 UCAGUUUAUACCCUAGUUAtt SEQ ID NO: 460UAGGCUGGGAGACUGAAGAtt SEQ ID NO: 461 GACUCAGCCCGGGUGGGGCtt SEQ ID NO:462 AAAUGAUUGGCCCCAGUCCtt SEQ ID NO: 463 AUGAUUGGCCCCAGUCCCCtt SEQ IDNO: 464 UCUGGGAGGCCCUGAGACAtt SEQ ID NO: 465 UCUAUUGCUUCACCAUGGCtt SEQID NO: 466 UUUUUCUCUUCCUUUUAGUtt SEQ ID NO: 467 GGAUCCCUGAUCCCAUUUUttSEQ ID NO: 468 GUUAGGGUUUAGGCAUCAUtt SEQ ID NO: 469UGCUGACACUUUUUCAGGGtt SEQ ID NO: 470 AAAUAUUUCUUUAAAAGAAtt SEQ ID NO:471 AUAUUUCUUUAAAAGAAGGtt SEQ ID NO: 472 AAGAAGGAUGAACAAUUAUtt SEQ IDNO: 473 GAAGGAUGAACAAUUAUAUtt SEQ ID NO: 474 GGAUGAACAAUUAUAUUUAtt SEQID NO: 475 CAAUUAUAUUUAUAUUUCAtt SEQ ID NO: 476 UUAUAUUUAUAUUUCAGGUttSEQ ID NO: 477 UAGUAGAGUUGGCUUUUUUtt SEQ ID NO: 478UGACAGUGCUAAAAAAAAAtt SEQ ID NO: 479 AAAAAAAAAGCAUUUUUUUtt SEQ ID NO:480 AAAAAAAGCAUUUUUUUUUtt SEQ ID NO: 481 AAAAAGCAUUUUUUUUUUAtt SEQ IDNO: 482 AAAGCAUUUUUUUUUUAUGtt SEQ ID NO: 483 AGCAUUUUUUUUUUAUGAUtt SEQID NO: 484 CGUUAUUUGUAAUUUAGUUtt SEQ ID NO: 485 UUUAGUUUGUAGCUCAUUAttSEQ ID NO: 486 AAAAAUGUGCCUAGUUUUAtt SEQ ID NO: 487AAAUGUGCCUAGUUUUAUAtt SEQ ID NO: 488 AUGUGCCUAGUUUUAUAAAtt

TABLE 6 Candidate siRNAs for ERBB3, SEQ ID NOs: 489-568 are based onNM_001005915 and SEQ ID NOs: 569-1120 are based on NM_001982. SEQ ID NO:489 CGGCAGCGGAGGUUGCAAAtt SEQ ID NO: 490 GCGGCGACGGCAGCGGAGGtt SEQ IDNO: 491 CACCUGAACCGCUGGCGAAtt SEQ ID NO: 492 CAGCACCUGCAGAGCGUCGtt SEQID NO: 493 AGGACACACUGCCUGAGAGtt SEQ ID NO: 494 GCCGGUCACACUCAGGCCAttSEQ ID NO: 495 GUACAGUGUCUGGUAUUGGtt SEQ ID NO: 496GCUUGUACAGUGUCUGGUAtt SEQ ID NO: 497 CUCACACCUCUCGUAGAGCtt SEQ ID NO:498 CGUGAGCACAAUCUCAAGGtt SEQ ID NO: 499 CAGGAAGGAGAGGUCGGCAtt SEQ IDNO: 500 CGAGGACAUAGCCUGUCACtt SEQ ID NO: 501 UGGUAGAGUAGAGAAUUCAtt SEQID NO: 502 GCAAUGGUAGAGUAGAGAAtt SEQ ID NO: 503 CCCUCGCACCACGCGGAGGttSEQ ID NO: 504 CAUGACGAAGAUGGCAAACtt SEQ ID NO: 505GCUGGAGUUGGUGUUAUAGtt SEQ ID NO: 506 AGCGUGGCUGGAGUUGGUGtt SEQ ID NO:507 GCGCAGAGCGUGGCUGGAGtt SEQ ID NO: 508 CAUCAAGGAGGUACCAGUCtt SEQ IDNO: 509 GCACUUAGAGUGAGCAGUCtt SEQ ID NO: 510 GGCACCUUGGAAGAGGCACtt SEQID NO: 511 GGCCAAGGUGACAGGCACCtt SEQ ID NO: 512 CUUAGGGAGCAAUGGACCUttSEQ ID NO: 513 ACUGGGGGCCCUCUAUUGCtt SEQ ID NO: 514CCCUACUGGGGGCCCUCUAtt SEQ ID NO: 515 ACAAGGACACAGGGUUCCUtt SEQ ID NO:516 GCCCCACAAGGACACAGGGtt SEQ ID NO: 517 UUUGAAAUUAGAAAAACGGtt SEQ IDNO: 518 GGUACACUGUACUUUGAAAtt SEQ ID NO: 519 GCCUCCGGUACACUGUACUtt SEQID NO: 520 GCCUCCCAAAAUGCUGGGAtt SEQ ID NO: 521 CUCAAGUGAUCUGCCCUCCttSEQ ID NO: 522 GAGACAGGGUUUCGCCAUGtt SEQ ID NO: 523UUUUUAGUAGAGACAGGGUtt SEQ ID NO: 524 AUUUUAUUUUUUUGUAUUUtt SEQ ID NO:525 UUAUUUUAUUUUUUUGUAUtt SEQ ID NO: 526 UUUAUUUUAUUUUAUUUUUtt SEQ IDNO: 527 UUUUUAUUUUAUUUUAUUUtt SEQ ID NO: 528 AUUUUUUAUUUUAUUUUAUtt SEQID NO: 529 UUUGCAACCUCCGCUGCCGtt SEQ ID NO: 530 CCUCCGCUGCCGUCGCCGCttSEQ ID NO: 531 UUCGCCAGCGGUUCAGGUGtt SEQ ID NO: 532CGACGCUCUGCAGGUGCUGtt SEQ ID NO: 533 CUCUCAGGCAGUGUGUCCUtt SEQ ID NO:534 UGGCCUGAGUGUGACCGGCtt SEQ ID NO: 535 CCAAUACCAGACACUGUACtt SEQ IDNO: 536 UACCAGACACUGUACAAGCtt SEQ ID NO: 537 GCUCUACGAGAGGUGUGAGtt SEQID NO: 538 CCUUGAGAUUGUGCUCACGtt SEQ ID NO: 539 UGCCGACCUCUCCUUCCUGttSEQ ID NO: 540 GUGACAGGCUAUGUCCUCGtt SEQ ID NO: 541UGAAUUCUCUACUCUACCAtt SEQ ID NO: 542 UUCUCUACUCUACCAUUGCtt SEQ ID NO:543 CCUCCGCGUGGUGCGAGGGtt SEQ ID NO: 544 GUUUGCCAUCUUCGUCAUGtt SEQ IDNO: 545 CUAUAACACCAACUCCAGCtt SEQ ID NO: 546 CACCAACUCCAGCCACGCUtt SEQID NO: 547 CUCCAGCCACGCUCUGCGCtt SEQ ID NO: 548 GACUGGUACCUCCUUGAUGttSEQ ID NO: 549 GACUGCUCACUCUAAGUGCtt SEQ ID NO: 550GUGCCUCUUCCAAGGUGCCtt SEQ ID NO: 551 GGUGCCUGUCACCUUGGCCtt SEQ ID NO:552 AGGUCCAUUGCUCCCUAAGtt SEQ ID NO: 553 GCAAUAGAGGGCCCCCAGUtt SEQ IDNO: 554 UAGAGGGCCCCCAGUAGGGtt SEQ ID NO: 555 AGGAACCCUGUGUCCUUGUtt SEQID NO: 556 CCCUGUGUCCUUGUGGGGCtt SEQ ID NO: 557 CCGUUUUUCUAAUUUCAAAttSEQ ID NO: 558 UUUCAAAGUACAGUGUACCtt SEQ ID NO: 559AGUACAGUGUACCGGAGGCtt SEQ ID NO: 560 UCCCAGCAUUUUGGGAGGCtt SEQ ID NO:561 GGAGGGCAGAUCACUUGAGtt SEQ ID NO: 562 CAUGGCGAAACCCUGUCUCtt SEQ IDNO: 563 ACCCUGUCUCUACUAAAAAtt SEQ ID NO: 564 AAAUACAAAAAAAUAAAAUtt SEQID NO: 565 AUACAAAAAAAUAAAAUAAtt SEQ ID NO: 566 AAAAAUAAAAUAAAAUAAAttSEQ ID NO: 567 AAAUAAAAUAAAAUAAAAAtt SEQ ID NO: 568AUAAAAUAAAAUAAAAAAUtt SEQ ID NO: 569 CGGCAGCGGAGGUUGCAAAtt SEQ ID NO:570 GCGGCGACGGCAGCGGAGGtt SEQ ID NO: 571 CACCUGAACCGCUGGCGAAtt SEQ IDNO: 572 CAGCACCUGCAGAGCGUCGtt SEQ ID NO: 573 AGGACACACUGCCUGAGAGtt SEQID NO: 574 GCCGGUCACACUCAGGCCAtt SEQ ID NO: 575 GUACAGUGUCUGGUAUUGGttSEQ ID NO: 576 GCUUGUACAGUGUCUGGUAtt SEQ ID NO: 577CUCACACCUCUCGUAGAGCtt SEQ ID NO: 578 CGUGAGCACAAUCUCAAGGtt SEQ ID NO:579 CAGGAAGGAGAGGUCGGCAtt SEQ ID NO: 580 CGAGGACAUAGCCUGUCACtt SEQ IDNO: 581 UGGUAGAGUAGAGAAUUCAtt SEQ ID NO: 582 GCAAUGGUAGAGUAGAGAAtt SEQID NO: 583 CCCUCGCACCACGCGGAGGtt SEQ ID NO: 584 CAUGACGAAGAUGGCAAACttSEQ ID NO: 585 GCUGGAGUUGGUGUUAUAGtt SEQ ID NO: 586AGCGUGGCUGGAGUUGGUGtt SEQ ID NO: 587 GCGCAGAGCGUGGCUGGAGtt SEQ ID NO:588 GUGACAAAGCUUAUCGUUCtt SEQ ID NO: 589 CAUGUGACAAAGCUUAUCGtt SEQ IDNO: 590 UGUGUCCAUGUGACAAAGCtt SEQ ID NO: 591 ACGAUGUCCCUCCAGUCAAtt SEQID NO: 592 ACAGCUUCUGCCAUUGUCCtt SEQ ID NO: 593 GGGGGGACAGCUUCUGCCAttSEQ ID NO: 594 UCAUGACAGGGGGGACAGCtt SEQ ID NO: 595AGGACCCCAGCAUCGCCCCtt SEQ ID NO: 596 UGGUCAAUGUCUGGCAGUCtt SEQ ID NO:597 CUGAGGAGCACAGAUGGUCtt SEQ ID NO: 598 GGGCCCAAAGCAGUGACCAtt SEQ IDNO: 599 AUGGCAGCACUGGUUGGGGtt SEQ ID NO: 600 CUCAUCAUGGCAGCACUGGtt SEQID NO: 601 UACACAGGCUCCACUGUCAtt SEQ ID NO: 602 CAGCUGGAAAGUUAGCUUGttSEQ ID NO: 603 UUCCAGCUGGAAAGUUAGCtt SEQ ID NO: 604UUGGGUUCCAGCUGGAAAGtt SEQ ID NO: 605 ACUUGGUGUGGGGAUUGGGtt SEQ ID NO:606 CUGAUACUUGGUGUGGGGAtt SEQ ID NO: 607 AACUCCUCCAUACUGAUACtt SEQ IDNO: 608 UGUUUGAUCCACCACAAAGtt SEQ ID NO: 609 AGGCCCUGACACAGGAUGUtt SEQID NO: 610 AUUUUUAUCUACUUCCAUCtt SEQ ID NO: 611 UGAGCCCAUUUUUAUCUACttSEQ ID NO: 612 ACACAUCUUGAGCCCAUUUtt SEQ ID NO: 613UCACACAUCUUGAGCCCAUtt SEQ ID NO: 614 CCCACAAGGCUCACACAUCtt SEQ ID NO:615 GCCUGUUCCCUCACAGGCUtt SEQ ID NO: 616 AAGCGGCUCCCAGAGCCUGtt SEQ IDNO: 617 GUUCACAAAUCCAUCAAUGtt SEQ ID NO: 618 GCCCAGGAUCUUGGUGCAGtt SEQID NO: 619 GUCCAGGUUGCCCAGGAUCtt SEQ ID NO: 620 GGUGAUCAGAAAGUCCAGGttSEQ ID NO: 621 CUUGUGCCAGGGGUCUCCAtt SEQ ID NO: 622UGGGUCCAGGGCAGGGAUCtt SEQ ID NO: 623 UGUCCGGAAGACAUUGAGCtt SEQ ID NO:624 CCGUACUGUCCGGAAGACAtt SEQ ID NO: 625 GGGCGGCCAGGACUGGAUGtt SEQ IDNO: 626 AUUGGAAAAAACACUGAAGtt SEQ ID NO: 627 GCCUCCAAUGGUUGUCAAAtt SEQID NO: 628 AGGCUUCUGCCUCCAAUGGtt SEQ ID NO: 629 AAGCCCCGGUUGUAGAGGCttSEQ ID NO: 630 CAACAAUGAGAAGCCCCGGtt SEQ ID NO: 631AGAUGUGACAUUCAAGUUCtt SEQ ID NO: 632 CAGAGAUGUGACAUUCAAGtt SEQ ID NO:633 GAAGCCCAGAGAUGUGACAtt SEQ ID NO: 634 ACGCCCAGCACUAAUUUCCtt SEQ IDNO: 635 AGAUACGCCCAGCACUAAUtt SEQ ID NO: 636 CAGAGCUGCCUAUUGGCACtt SEQID NO: 637 GUGGUAGCAGAGCUGCCUAtt SEQ ID NO: 638 CCGAAGCACCUUGGUCCAGttSEQ ID NO: 639 CGUAGGCCCCCGAAGCACCtt SEQ ID NO: 640GCUUGAUGUCUAGUCGCUCtt SEQ ID NO: 641 UCUGCGCGGCCGAUUAUGCtt SEQ ID NO:642 GCAGUCUCUGCGCGGCCGAtt SEQ ID NO: 643 GCACAGUGGGUCACACACUtt SEQ IDNO: 644 ACACCUCCUCGGCUAUAAUtt SEQ ID NO: 645 AGGCUCCCCAUUCAGAAAGtt SEQID NO: 646 AAAUUCUCGAGGCUCCCCAtt SEQ ID NO: 647 AUUCGGCCUCAUGGGCAAAttSEQ ID NO: 648 CCGGGUGGCAGGAGAAGCAtt SEQ ID NO: 649UGCCCUCCAUGGGUUGGCAtt SEQ ID NO: 650 UGGCAGUGCCCUCCAUGGGtt SEQ ID NO:651 AGUAUCAGAGCCCGAGCCAtt SEQ ID NO: 652 CAUCUCGAAAAUGGGCACAtt SEQ IDNO: 653 GUACUUGUAGAUUGGGCCCtt SEQ ID NO: 654 ACAUCUGGGUACUUGUAGAtt SEQID NO: 655 AUUCUGAACAUCUGGGUACtt SEQ ID NO: 656 AUGGCAGGGCCGACAUUCAttSEQ ID NO: 657 UCUCAUGGCAGGGCCGACAtt SEQ ID NO: 658UUUACACCCCUGGGUGCAGtt SEQ ID NO: 659 GUCUUGAAGCUCUGGUCCUtt SEQ ID NO:660 GUGUUUGUCCUAAACAGUCtt SEQ ID NO: 661 UGCCGAUCAGCACCAGUGUtt SEQ IDNO: 662 AGCCAUUGUCAGAUGGGUUtt SEQ ID NO: 663 AAAGCCAUUGUCAGAUGGGtt SEQID NO: 664 GCUAUCACUGUCAAAGCCAtt SEQ ID NO: 665 UCGCCUCAUAGCCCUUUUAttSEQ ID NO: 666 GUAUCGCCUCAUAGCCCUUtt SEQ ID NO: 667AAGUAUCGCCUCAUAGCCCtt SEQ ID NO: 668 GCUCUAUGCUCUCACCCCGtt SEQ ID NO:669 GGCCAAGACUUUGUUAGCCtt SEQ ID NO: 670 GAUUCUGGCCAAGACUUUGtt SEQ IDNO: 671 GAAGAUUCUGGCCAAGACUtt SEQ ID NO: 672 AGCUCUGUCUCUUUGAAGAtt SEQID NO: 673 CUUCCUUAGCUCUGUCUCUtt SEQ ID NO: 674 CCAAGCACUUUAAGCUUCCttSEQ ID NO: 675 CGAGCCAAGCACUUUAAGCtt SEQ ID NO: 676GACACCCGAGCCAAGCACUtt SEQ ID NO: 677 CACACUCCUUUGUGCACAGtt SEQ ID NO:678 CUCAGGGAUCCACACUCCUtt SEQ ID NO: 679 AGACUGGAAUCUUGAUUGAtt SEQ IDNO: 680 AUGCAGACUGGAAUCUUGAtt SEQ ID NO: 681 UUUAAUGCAGACUGGAAUCtt SEQID NO: 682 ACUCUUGUCCUCAAUGACUtt SEQ ID NO: 683 AAAACUCUGCCGUCCACUCttSEQ ID NO: 684 GCAUAUGAUCUGUCACAGCtt SEQ ID NO: 685GGGCAUAGUCCCAGCAGCCtt SEQ ID NO: 686 GAGAACCCAGAGGCAAAUAtt SEQ ID NO:687 GCCCCAGUGCCCCCCGGUGtt SEQ ID NO: 688 GGCAAUUUGUACUCCCCAGtt SEQ IDNO: 689 AGUACAUUCCCUUGGCAAUtt SEQ ID NO: 690 CUCAAGGUAGUACAUUCCCtt SEQID NO: 691 UGUUCCUCAAGGUAGUACAtt SEQ ID NO: 692 UUCUAUGCACCAUACCAUGttSEQ ID NO: 693 ACGUUUCGGGCAGCCAGGUtt SEQ ID NO: 694GGUGACUUGAGUAGCACGUtt SEQ ID NO: 695 CUGAACCUGACUGGGUGACtt SEQ ID NO:696 CUCACUGUAUAGCAGCUGCtt SEQ ID NO: 697 CAUCCACUUAAUUGGAGUCtt SEQ IDNO: 698 UCAAGGGCCAUCCACUUAAtt SEQ ID NO: 699 ACUCUCAAGGGCCAUCCACtt SEQID NO: 700 AUCACUCUGGUGUGUGUAUtt SEQ ID NO: 701 UCUCUAGCAGGUCUGGUACttSEQ ID NO: 702 CUGUGCCAACCGCUCCCCCtt SEQ ID NO: 703AUCACCAUGUAGACAUCAAtt SEQ ID NO: 704 CUCAUCAAUCAUCCAACACtt SEQ ID NO:705 UUUAAAGGUUGGGCGAAUGtt SEQ ID NO: 706 UUGGCUAGUUCUUUAAAGGtt SEQ IDNO: 707 GAACUCAUUGGCUAGUUCUtt SEQ ID NO: 708 UGGUGAACUCAUUGGCUAGtt SEQID NO: 709 GGCCAUCCUGGUGAACUCAtt SEQ ID NO: 710 CCAGGCCCACUCUCUCUCUttSEQ ID NO: 711 GGCUCUGGCCCAGGGGCUAtt SEQ ID NO: 712ACUUCCUCUAGCUUCUUGUtt SEQ ID NO: 713 CUCUACUUCCUCUAGCUUCtt SEQ ID NO:714 CAGCUCUACUUCCUCUAGCtt SEQ ID NO: 715 GUUCUGGCUCCAGCUCUACtt SEQ IDNO: 716 AGUCUAGGUCUAGGUCUAGtt SEQ ID NO: 717 CCAGGUUGUCCUCCUCUGCtt SEQID NO: 718 CAGUGUGGUGGUUGCCAGGtt SEQ ID NO: 719 GCGGAGCCCAGUGUGGUGGttSEQ ID NO: 720 CCACGUGGCCGAUUAAGUGtt SEQ ID NO: 721CUGGCUCCCACGUGGCCGAtt SEQ ID NO: 722 AUGUAUCCAGAUGAUGGACtt SEQ ID NO:723 CUCCCCAAGAUUACCCUGGtt SEQ ID NO: 724 CUGGCAAGACUCCCCAAGAtt SEQ IDNO: 725 AGACUGGACGGGGGCACCGtt SEQ ID NO: 726 GCCAGGCAUCCCCGUGGCAtt SEQID NO: 727 AGCUCAGCCUCAGAGCCUGtt SEQ ID NO: 728 GCUCCUACACAUUGACACUttSEQ ID NO: 729 CUGCUCCGGCUCCUACACAtt SEQ ID NO: 730CAUAACCGUUGACAUCCUCtt SEQ ID NO: 731 AUCUGGCAUGACAUAACCGtt SEQ ID NO:732 CCGGGAGGAGGGAGUACCUtt SEQ ID NO: 733 CCACUGAAGAAAGGGUGCCtt SEQ IDNO: 734 CCUCAUCUUCAUCUUCUUCtt SEQ ID NO: 735 ACUCCUCAUCUUCAUCUUCtt SEQID NO: 736 CAUACUCCUCAUCUUCAUCtt SEQ ID NO: 737 UGUAUUCAUACUCCUCAUCttSEQ ID NO: 738 UUCUCCUCCGGUUCAUGUAtt SEQ ID NO: 739ACUGUGCCUUCUCCUCCGGtt SEQ ID NO: 740 GGAUGAGGUGGACUGUGCCtt SEQ ID NO:741 CCCAGCUCCUCAAGGGAACtt SEQ ID NO: 742 UCAUAGUCUUCAUCUGGAGtt SEQ IDNO: 743 GAUUCAUAUAUUCAUAGUCtt SEQ ID NO: 744 CUCGUUGCCGAUUCAUAUAtt SEQID NO: 745 ACCUCCAUCUCGUUGCCGAtt SEQ ID NO: 746 CAGGACCACCUCCAUCUCGttSEQ ID NO: 747 CUCUCAUCUCUUCAUACCCtt SEQ ID NO: 748CCUGAAAAGCUCUCAUCUCtt SEQ ID NO: 749 UCUAAGCUACGUAGAGUUUtt SEQ ID NO:750 CCUCUAAGCUACGUAGAGUtt SEQ ID NO: 751 GCUAUGCCAGUAAUCAGGGtt SEQ IDNO: 752 CGUUCUCUGGGCAUUAGCCtt SEQ ID NO: 753 GAGUUACGUUCUCUGGGCAtt SEQID NO: 754 ACAGGGAGCAGGAGUUACGtt SEQ ID NO: 755 GUGCCACAGGGAGCAGGAGttSEQ ID NO: 756 CUAAAGGCACUAGCUGCCAtt SEQ ID NO: 757CUCCAAAGAUUGAAUGGAAtt SEQ ID NO: 758 GUUUAAAAGCCUCCAAAGAtt SEQ ID NO:759 GAAUUUUGUGUCAAAAUGUtt SEQ ID NO: 760 GCUACAUACCAUAAGAAUUtt SEQ IDNO: 761 UGGCUACAUACCAUAAGAAtt SEQ ID NO: 762 AGGAAAACCUUUCCUGGGGtt SEQID NO: 763 CACAAAAUAAGGAAAACCUtt SEQ ID NO: 764 GGGAUAUGGAGAGUAAUCCttSEQ ID NO: 765 GGCACACAUAAGAGCCUAGtt SEQ ID NO: 766UUUCCUCCCUUUCCUCUUCtt SEQ ID NO: 767 AGGUUUCCUCCCUUUCCUCtt SEQ ID NO:768 UCUGCUAGGUUUCCUCCCUtt SEQ ID NO: 769 ACACUUUCCUCUGCUAGGUtt SEQ IDNO: 770 CAUAAACCAAAAUUACACUtt SEQ ID NO: 771 UAAGAGUCAUAAACCAAAAtt SEQID NO: 772 CUUCUGUCUUUCUAGGGGGtt SEQ ID NO: 773 AGAUUUUAAGCUUCUGUCUttSEQ ID NO: 774 UUCUUCACAGAUUUUAAGCtt SEQ ID NO: 775ACCUCUUUCUUCACAGAUUtt SEQ ID NO: 776 UAACCUCUUUCUUCACAGAtt SEQ ID NO:777 UCUACUCCUAACCUCUUUCtt SEQ ID NO: 778 AUAUCUACUCCUAACCUCUtt SEQ IDNO: 779 CUCAUAGUUAAGUGCUGAAtt SEQ ID NO: 780 UAUGAUGCCUGGCUCAUAGtt SEQID NO: 781 GAGAUAAUGUAGGUGAAGUtt SEQ ID NO: 782 UGUAUGUCACAGAAUUGUUttSEQ ID NO: 783 UAUGUAUGUCACAGAAUUGtt SEQ ID NO: 784UAAUAUGUAUGUCACAGAAtt SEQ ID NO: 785 CACCAUGCCCGACUUCCCUtt SEQ ID NO:786 AUGAGCCACCAUGCCCGACtt SEQ ID NO: 787 GCCUCCCAAAGUGCUGAGAtt SEQ IDNO: 788 UCCUUGCCUCAGGUAAUCCtt SEQ ID NO: 789 UAAGCUGGUCUCAAACUCCtt SEQID NO: 790 AGAUGGGGGUCUUACUAUGtt SEQ ID NO: 791 UUUUAAAGAGAUGGGGGUCttSEQ ID NO: 792 UUUUUUUUUUUUUUUUUUUtt SEQ ID NO: 793GUUUUUUUUUUUUUUUUUUtt SEQ ID NO: 794 AAGUUUUUUUUUUUUUUUUtt SEQ ID NO:795 UAAAGUUUUUUUUUUUUUUtt SEQ ID NO: 796 UCUAAAGUUUUUUUUUUUUtt SEQ IDNO: 797 GUUCUAAAGUUUUUUUUUUtt SEQ ID NO: 798 CAGUUCUAAAGUUUUUUUUtt SEQID NO: 799 CCCAGUUCUAAAGUUUUUUtt SEQ ID NO: 800 CACCCAGUUCUAAAGUUUUttSEQ ID NO: 801 UGCACCCAGUUCUAAAGUUtt SEQ ID NO: 802ACUGCACCCAGUUCUAAAGtt SEQ ID NO: 803 CAUGAGCCACUGCACCCAGtt SEQ ID NO:804 CCCAAAGUGCUGGCUGGGAtt SEQ ID NO: 805 AUUCUGGGCUCAAGUGAUCtt SEQ IDNO: 806 UCCAUAGGCUUAUCUCUAAtt SEQ ID NO: 807 UUGCUAUGUUUCCAUAGGCtt SEQID NO: 808 AGACAGUGUCUUGCUAUGUtt SEQ ID NO: 809 CCCCUGUAGAGACAGUGUCttSEQ ID NO: 810 CUCAGUUUCUUUUUUUUUUtt SEQ ID NO: 811GGCUCAGUUUCUUUUUUUUtt SEQ ID NO: 812 AAGGCUCAGUUUCUUUUUUtt SEQ ID NO:813 UUAAGGCUCAGUUUCUUUUtt SEQ ID NO: 814 CUUUAAGGCUCAGUUUCUUtt SEQ IDNO: 815 CUCUUUAAGGCUCAGUUUCtt SEQ ID NO: 816 CAUCUCUUUAAGGCUCAGUtt SEQID NO: 817 CUUAAUUUAUUUCAUCUCUtt SEQ ID NO: 818 GAUCUACUGCUUAAUUUAUttSEQ ID NO: 819 CCUGGAUCUACUGCUUAAUtt SEQ ID NO: 820UGCAUCCUGGAUCUACUGCtt SEQ ID NO: 821 CACAGGAAUUGGGAGGAUUtt SEQ ID NO:822 UGCACAGGAAUUGGGAGGAtt SEQ ID NO: 823 AAGAGCACAUGCACAGGAAtt SEQ IDNO: 824 AUCAGUUUUUCUUGGCACCtt SEQ ID NO: 825 UAACUUAAAUCAGUUUUUCtt SEQID NO: 826 CUGUAACUUAAAUCAGUUUtt SEQ ID NO: 827 GGCUGUAACUUAAAUCAGUttSEQ ID NO: 828 CUUAAACAAGGGCUGUAACtt SEQ ID NO: 829AAACAAGAAACAGUGCCCCtt SEQ ID NO: 830 CUGUUGGGGUUAGACUUGAtt SEQ ID NO:831 GUGGCUGUUGGGGUUAGACtt SEQ ID NO: 832 GAGGAUGUGGCUGUUGGGGtt SEQ IDNO: 833 GUAUAGGAGGAUGUGGCUGtt SEQ ID NO: 834 UGACUACCCCCACCACCACtt SEQID NO: 835 GAUGUCCAGUUAUUUUUCCtt SEQ ID NO: 836 CAAAGAUGUCCAGUUAUUUttSEQ ID NO: 837 CACAAAGAUGUCCAGUUAUtt SEQ ID NO: 838UUUACACAAAGAUGUCCAGtt SEQ ID NO: 839 GGCACAUGUGGAUUAUGGUtt SEQ ID NO:840 CAUUUACGGCACAUGUGGAtt SEQ ID NO: 841 GAUAAGGAGUGAAGAUCAUtt SEQ IDNO: 842 CUUGGGGAUCCUUGUGAAUtt SEQ ID NO: 843 AAGUGGAUCUUGGGGAUCCtt SEQID NO: 844 UGGCUUCUAAAAGUGGAUCtt SEQ ID NO: 845 UUUGCAACCUCCGCUGCCGttSEQ ID NO: 846 CCUCCGCUGCCGUCGCCGCtt SEQ ID NO: 847UUCGCCAGCGGUUCAGGUGtt SEQ ID NO: 848 CGACGCUCUGCAGGUGCUGtt SEQ ID NO:849 CUCUCAGGCAGUGUGUCCUtt SEQ ID NO: 850 UGGCCUGAGUGUGACCGGCtt SEQ IDNO: 851 CCAAUACCAGACACUGUACtt SEQ ID NO: 852 UACCAGACACUGUACAAGCtt SEQID NO: 853 GCUCUACGAGAGGUGUGAGtt SEQ ID NO: 854 CCUUGAGAUUGUGCUCACGttSEQ ID NO: 855 UGCCGACCUCUCCUUCCUGtt SEQ ID NO: 856GUGACAGGCUAUGUCCUCGtt SEQ ID NO: 857 UGAAUUCUCUACUCUACCAtt SEQ ID NO:858 UUCUCUACUCUACCAUUGCtt SEQ ID NO: 859 CCUCCGCGUGGUGCGAGGGtt SEQ IDNO: 860 GUUUGCCAUCUUCGUCAUGtt SEQ ID NO: 861 CUAUAACACCAACUCCAGCtt SEQID NO: 862 CACCAACUCCAGCCACGCUtt SEQ ID NO: 863 CUCCAGCCACGCUCUGCGCttSEQ ID NO: 864 GAACGAUAAGCUUUGUCACtt SEQ ID NO: 865CGAUAAGCUUUGUCACAUGtt SEQ ID NO: 866 GCUUUGUCACAUGGACACAtt SEQ ID NO:867 UUGACUGGAGGGACAUCGUtt SEQ ID NO: 868 GGACAAUGGCAGAAGCUGUtt SEQ IDNO: 869 UGGCAGAAGCUGUCCCCCCtt SEQ ID NO: 870 GCUGUCCCCCCUGUCAUGAtt SEQID NO: 871 GGGGCGAUGCUGGGGUCCUtt SEQ ID NO: 872 GACUGCCAGACAUUGACCAttSEQ ID NO: 873 GACCAUCUGUGCUCCUCAGtt SEQ ID NO: 874UGGUCACUGCUUUGGGCCCtt SEQ ID NO: 875 CCCCAACCAGUGCUGCCAUtt SEQ ID NO:876 CCAGUGCUGCCAUGAUGAGtt SEQ ID NO: 877 UGACAGUGGAGCCUGUGUAtt SEQ IDNO: 878 CAAGCUAACUUUCCAGCUGtt SEQ ID NO: 879 GCUAACUUUCCAGCUGGAAtt SEQID NO: 880 CUUUCCAGCUGGAACCCAAtt SEQ ID NO: 881 CCCAAUCCCCACACCAAGUttSEQ ID NO: 882 UCCCCACACCAAGUAUCAGtt SEQ ID NO: 883GUAUCAGUAUGGAGGAGUUtt SEQ ID NO: 884 CUUUGUGGUGGAUCAAACAtt SEQ ID NO:885 ACAUCCUGUGUCAGGGCCUtt SEQ ID NO: 886 GAUGGAAGUAGAUAAAAAUtt SEQ IDNO: 887 GUAGAUAAAAAUGGGCUCAtt SEQ ID NO: 888 AAAUGGGCUCAAGAUGUGUtt SEQID NO: 889 AUGGGCUCAAGAUGUGUGAtt SEQ ID NO: 890 GAUGUGUGAGCCUUGUGGGttSEQ ID NO: 891 AGCCUGUGAGGGAACAGGCtt SEQ ID NO: 892CAGGCUCUGGGAGCCGCUUtt SEQ ID NO: 893 CAUUGAUGGAUUUGUGAACtt SEQ ID NO:894 CUGCACCAAGAUCCUGGGCtt SEQ ID NO: 895 GAUCCUGGGCAACCUGGACtt SEQ IDNO: 896 CCUGGACUUUCUGAUCACCtt SEQ ID NO: 897 UGGAGACCCCUGGCACAAGtt SEQID NO: 898 GAUCCCUGCCCUGGACCCAtt SEQ ID NO: 899 GCUCAAUGUCUUCCGGACAttSEQ ID NO: 900 UGUCUUCCGGACAGUACGGtt SEQ ID NO: 901CAUCCAGUCCUGGCCGCCCtt SEQ ID NO: 902 CUUCAGUGUUUUUUCCAAUtt SEQ ID NO:903 UUUGACAACCAUUGGAGGCtt SEQ ID NO: 904 CCAUUGGAGGCAGAAGCCUtt SEQ IDNO: 905 GCCUCUACAACCGGGGCUUtt SEQ ID NO: 906 CCGGGGCUUCUCAUUGUUGtt SEQID NO: 907 GAACUUGAAUGUCACAUCUtt SEQ ID NO: 908 CUUGAAUGUCACAUCUCUGttSEQ ID NO: 909 UGUCACAUCUCUGGGCUUCtt SEQ ID NO: 910GGAAAUUAGUGCUGGGCGUtt SEQ ID NO: 911 AUUAGUGCUGGGCGUAUCUtt SEQ ID NO:912 GUGCCAAUAGGCAGCUCUGtt SEQ ID NO: 913 UAGGCAGCUCUGCUACCACtt SEQ IDNO: 914 CUGGACCAAGGUGCUUCGGtt SEQ ID NO: 915 GGUGCUUCGGGGGCCUACGtt SEQID NO: 916 GAGCGACUAGACAUCAAGCtt SEQ ID NO: 917 GCAUAAUCGGCCGCGCAGAttSEQ ID NO: 918 UCGGCCGCGCAGAGACUGCtt SEQ ID NO: 919AGUGUGUGACCCACUGUGCtt SEQ ID NO: 920 AUUAUAGCCGAGGAGGUGUtt SEQ ID NO:921 CUUUCUGAAUGGGGAGCCUtt SEQ ID NO: 922 UGGGGAGCCUCGAGAAUUUtt SEQ IDNO: 923 UUUGCCCAUGAGGCCGAAUtt SEQ ID NO: 924 UGCUUCUCCUGCCACCCGGtt SEQID NO: 925 UGCCAACCCAUGGAGGGCAtt SEQ ID NO: 926 CCCAUGGAGGGCACUGCCAttSEQ ID NO: 927 UGGCUCGGGCUCUGAUACUtt SEQ ID NO: 928UGUGCCCAUUUUCGAGAUGtt SEQ ID NO: 929 GGGCCCAAUCUACAAGUACtt SEQ ID NO:930 UCUACAAGUACCCAGAUGUtt SEQ ID NO: 931 GUACCCAGAUGUUCAGAAUtt SEQ IDNO: 932 UGAAUGUCGGCCCUGCCAUtt SEQ ID NO: 933 UGUCGGCCCUGCCAUGAGAtt SEQID NO: 934 CUGCACCCAGGGGUGUAAAtt SEQ ID NO: 935 AGGACCAGAGCUUCAAGACttSEQ ID NO: 936 GACUGUUUAGGACAAACACtt SEQ ID NO: 937ACACUGGUGCUGAUCGGCAtt SEQ ID NO: 938 AACCCAUCUGACAAUGGCUtt SEQ ID NO:939 CCCAUCUGACAAUGGCUUUtt SEQ ID NO: 940 UGGCUUUGACAGUGAUAGCtt SEQ IDNO: 941 UAAAAGGGCUAUGAGGCGAtt SEQ ID NO: 942 AAGGGCUAUGAGGCGAUACtt SEQID NO: 943 GGGCUAUGAGGCGAUACUUtt SEQ ID NO: 944 CGGGGUGAGAGCAUAGAGCttSEQ ID NO: 945 GGCUAACAAAGUCUUGGCCtt SEQ ID NO: 946CAAAGUCUUGGCCAGAAUCtt SEQ ID NO: 947 AGUCUUGGCCAGAAUCUUCtt SEQ ID NO:948 UCUUCAAAGAGACAGAGCUtt SEQ ID NO: 949 AGAGACAGAGCUAAGGAAGtt SEQ IDNO: 950 GGAAGCUUAAAGUGCUUGGtt SEQ ID NO: 951 GCUUAAAGUGCUUGGCUCGtt SEQID NO: 952 AGUGCUUGGCUCGGGUGUCtt SEQ ID NO: 953 CUGUGCACAAAGGAGUGUGttSEQ ID NO: 954 AGGAGUGUGGAUCCCUGAGtt SEQ ID NO: 955UCAAUCAAGAUUCCAGUCUtt SEQ ID NO: 956 UCAAGAUUCCAGUCUGCAUtt SEQ ID NO:957 GAUUCCAGUCUGCAUUAAAtt SEQ ID NO: 958 AGUCAUUGAGGACAAGAGUtt SEQ IDNO: 959 GAGUGGACGGCAGAGUUUUtt SEQ ID NO: 960 GCUGUGACAGAUCAUAUGCtt SEQID NO: 961 GGCUGCUGGGACUAUGCCCtt SEQ ID NO: 962 UAUUUGCCUCUGGGUUCUCttSEQ ID NO: 963 CACCGGGGGGCACUGGGGCtt SEQ ID NO: 964CUGGGGAGUACAAAUUGCCtt SEQ ID NO: 965 AUUGCCAAGGGAAUGUACUtt SEQ ID NO:966 GGGAAUGUACUACCUUGAGtt SEQ ID NO: 967 UGUACUACCUUGAGGAACAtt SEQ IDNO: 968 CAUGGUAUGGUGCAUAGAAtt SEQ ID NO: 969 ACCUGGCUGCCCGAAACGUtt SEQID NO: 970 ACGUGCUACUCAAGUCACCtt SEQ ID NO: 971 GUCACCCAGUCAGGUUCAGttSEQ ID NO: 972 GCAGCUGCUAUACAGUGAGtt SEQ ID NO: 973GACUCCAAUUAAGUGGAUGtt SEQ ID NO: 974 UUAAGUGGAUGGCCCUUGAtt SEQ ID NO:975 GUGGAUGGCCCUUGAGAGUtt SEQ ID NO: 976 AUACACACACCAGAGUGAUtt SEQ IDNO: 977 GUACCAGACCUGCUAGAGAtt SEQ ID NO: 978 GGGGGAGCGGUUGGCACAGtt SEQID NO: 979 UUGAUGUCUACAUGGUGAUtt SEQ ID NO: 980 GUGUUGGAUGAUUGAUGAGttSEQ ID NO: 981 CAUUCGCCCAACCUUUAAAtt SEQ ID NO: 982CCUUUAAAGAACUAGCCAAtt SEQ ID NO: 983 AGAACUAGCCAAUGAGUUCtt SEQ ID NO:984 CUAGCCAAUGAGUUCACCAtt SEQ ID NO: 985 UGAGUUCACCAGGAUGGCCtt SEQ IDNO: 986 AGAGAGAGAGUGGGCCUGGtt SEQ ID NO: 987 UAGCCCCUGGGCCAGAGCCtt SEQID NO: 988 ACAAGAAGCUAGAGGAAGUtt SEQ ID NO: 989 GAAGCUAGAGGAAGUAGAGttSEQ ID NO: 990 GCUAGAGGAAGUAGAGCUGtt SEQ ID NO: 991GUAGAGCUGGAGCCAGAACtt SEQ ID NO: 992 CUAGACCUAGACCUAGACUtt SEQ ID NO:993 GCAGAGGAGGACAACCUGGtt SEQ ID NO: 994 CCUGGCAACCACCACACUGtt SEQ IDNO: 995 CCACCACACUGGGCUCCGCtt SEQ ID NO: 996 CACUUAAUCGGCCACGUGGtt SEQID NO: 997 UCGGCCACGUGGGAGCCAGtt SEQ ID NO: 998 GUCCAUCAUCUGGAUACAUttSEQ ID NO: 999 CCAGGGUAAUCUUGGGGAGtt SEQ ID NO: 1000UCUUGGGGAGUCUUGCCAGtt SEQ ID NO: 1001 CGGUGCCCCCGUCCAGUCUtt SEQ ID NO:1002 UGCCACGGGGAUGCCUGGCtt SEQ ID NO: 1003 CAGGCUCUGAGGCUGAGCUtt SEQ IDNO: 1004 AGUGUCAAUGUGUAGGAGCtt SEQ ID NO: 1005 UGUGUAGGAGCCGGAGCAGtt SEQID NO: 1006 GAGGAUGUCAACGGUUAUGtt SEQ ID NO: 1007 CGGUUAUGUCAUGCCAGAUttSEQ ID NO: 1008 AGGUACUCCCUCCUCCCGGtt SEQ ID NO: 1009GGCACCCUUUCUUCAGUGGtt SEQ ID NO: 1010 GAAGAAGAUGAAGAUGAGGtt SEQ ID NO:1011 GAAGAUGAAGAUGAGGAGUtt SEQ ID NO: 1012 GAUGAAGAUGAGGAGUAUGtt SEQ IDNO: 1013 GAUGAGGAGUAUGAAUACAtt SEQ ID NO: 1014 UACAUGAACCGGAGGAGAAtt SEQID NO: 1015 CCGGAGGAGAAGGCACAGUtt SEQ ID NO: 1016 GGCACAGUCCACCUCAUCCttSEQ ID NO: 1017 GUUCCCUUGAGGAGCUGGGtt SEQ ID NO: 1018CUCCAGAUGAAGACUAUGAtt SEQ ID NO: 1019 GACUAUGAAUAUAUGAAUCtt SEQ ID NO:1020 UAUAUGAAUCGGCAACGAGtt SEQ ID NO: 1021 UCGGCAACGAGAUGGAGGUtt SEQ IDNO: 1022 CGAGAUGGAGGUGGUCCUGtt SEQ ID NO: 1023 GGGUAUGAAGAGAUGAGAGtt SEQID NO: 1024 GAGAUGAGAGCUUUUCAGGtt SEQ ID NO: 1025 AAACUCUACGUAGCUUAGAttSEQ ID NO: 1026 ACUCUACGUAGCUUAGAGGtt SEQ ID NO: 1027CCCUGAUUACUGGCAUAGCtt SEQ ID NO: 1028 GGCUAAUGCCCAGAGAACGtt SEQ ID NO:1029 UGCCCAGAGAACGUAACUCtt SEQ ID NO: 1030 CGUAACUCCUGCUCCCUGUtt SEQ IDNO: 1031 CUCCUGCUCCCUGUGGCACtt SEQ ID NO: 1032 UGGCAGCUAGUGCCUUUAGtt SEQID NO: 1033 UUCCAUUCAAUCUUUGGAGtt SEQ ID NO: 1034 UCUUUGGAGGCUUUUAAACttSEQ ID NO: 1035 ACAUUUUGACACAAAAUUCtt SEQ ID NO: 1036AAUUCUUAUGGUAUGUAGCtt SEQ ID NO: 1037 UUCUUAUGGUAUGUAGCCAtt SEQ ID NO:1038 CCCCAGGAAAGGUUUUCCUtt SEQ ID NO: 1039 AGGUUUUCCUUAUUUUGUGtt SEQ IDNO: 1040 GGAUUACUCUCCAUAUCCCtt SEQ ID NO: 1041 CUAGGCUCUUAUGUGUGCCtt SEQID NO: 1042 GAAGAGGAAAGGGAGGAAAtt SEQ ID NO: 1043 GAGGAAAGGGAGGAAACCUttSEQ ID NO: 1044 AGGGAGGAAACCUAGCAGAtt SEQ ID NO: 1045ACCUAGCAGAGGAAAGUGUtt SEQ ID NO: 1046 AGUGUAAUUUUGGUUUAUGtt SEQ ID NO:1047 UUUUGGUUUAUGACUCUUAtt SEQ ID NO: 1048 CCCCCUAGAAAGACAGAAGtt SEQ IDNO: 1049 AGACAGAAGCUUAAAAUCUtt SEQ ID NO: 1050 GCUUAAAAUCUGUGAAGAAtt SEQID NO: 1051 AAUCUGUGAAGAAAGAGGUtt SEQ ID NO: 1052 UCUGUGAAGAAAGAGGUUAttSEQ ID NO: 1053 GAAAGAGGUUAGGAGUAGAtt SEQ ID NO: 1054AGAGGUUAGGAGUAGAUAUtt SEQ ID NO: 1055 UUCAGCACUUAACUAUGAGtt SEQ ID NO:1056 CUAUGAGCCAGGCAUCAUAtt SEQ ID NO: 1057 ACUUCACCUACAUUAUCUCtt SEQ IDNO: 1058 AACAAUUCUGUGACAUACAtt SEQ ID NO: 1059 CAAUUCUGUGACAUACAUAtt SEQID NO: 1060 UUCUGUGACAUACAUAUUAtt SEQ ID NO: 1061 AGGGAAGUCGGGCAUGGUGttSEQ ID NO: 1062 GUCGGGCAUGGUGGCUCAUtt SEQ ID NO: 1063UCUCAGCACUUUGGGAGGCtt SEQ ID NO: 1064 GGAUUACCUGAGGCAAGGAtt SEQ ID NO:1065 GGAGUUUGAGACCAGCUUAtt SEQ ID NO: 1066 CAUAGUAAGACCCCCAUCUtt SEQ IDNO: 1067 GACCCCCAUCUCUUUAAAAtt SEQ ID NO: 1068 AAAAAAAAAAAAAAAAAAAtt SEQID NO: 1069 AAAAAAAAAAAAAAAAAACtt SEQ ID NO: 1070 AAAAAAAAAAAAAAAACUUttSEQ ID NO: 1071 AAAAAAAAAAAAAACUUUAtt SEQ ID NO: 1072AAAAAAAAAAAACUUUAGAtt SEQ ID NO: 1073 AAAAAAAAAACUUUAGAACtt SEQ ID NO:1074 AAAAAAAACUUUAGAACUGtt SEQ ID NO: 1075 AAAAAACUUUAGAACUGGGtt SEQ IDNO: 1076 AAAACUUUAGAACUGGGUGtt SEQ ID NO: 1077 AACUUUAGAACUGGGUGCAtt SEQID NO: 1078 CUUUAGAACUGGGUGCAGUtt SEQ ID NO: 1079 CUGGGUGCAGUGGCUCAUGttSEQ ID NO: 1080 UCCCAGCCAGCACUUUGGGtt SEQ ID NO: 1081GAUCACUUGAGCCCAGAAUtt SEQ ID NO: 1082 UUAGAGAUAAGCCUAUGGAtt SEQ ID NO:1083 GCCUAUGGAAACAUAGCAAtt SEQ ID NO: 1084 ACAUAGCAAGACACUGUCUtt SEQ IDNO: 1085 GACACUGUCUCUACAGGGGtt SEQ ID NO: 1086 AAAAAAAAAAGAAACUGAGtt SEQID NO: 1087 AAAAAAAAGAAACUGAGCCtt SEQ ID NO: 1088 AAAAAAGAAACUGAGCCUUttSEQ ID NO: 1089 AAAAGAAACUGAGCCUUAAtt SEQ ID NO: 1090AAGAAACUGAGCCUUAAAGtt SEQ ID NO: 1091 GAAACUGAGCCUUAAAGAGtt SEQ ID NO:1092 ACUGAGCCUUAAAGAGAUGtt SEQ ID NO: 1093 AGAGAUGAAAUAAAUUAAGtt SEQ IDNO: 1094 AUAAAUUAAGCAGUAGAUCtt SEQ ID NO: 1095 AUUAAGCAGUAGAUCCAGGtt SEQID NO: 1096 GCAGUAGAUCCAGGAUGCAtt SEQ ID NO: 1097 AAUCCUCCCAAUUCCUGUGttSEQ ID NO: 1098 UCCUCCCAAUUCCUGUGCAtt SEQ ID NO: 1099UUCCUGUGCAUGUGCUCUUtt SEQ ID NO: 1100 GGUGCCAAGAAAAACUGAUtt SEQ ID NO:1101 GAAAAACUGAUUUAAGUUAtt SEQ ID NO: 1102 AAACUGAUUUAAGUUACAGtt SEQ IDNO: 1103 ACUGAUUUAAGUUACAGCCtt SEQ ID NO: 1104 GUUACAGCCCUUGUUUAAGtt SEQID NO: 1105 GGGGCACUGUUUCUUGUUUtt SEQ ID NO: 1106 UCAAGUCUAACCCCAACAGttSEQ ID NO: 1107 GUCUAACCCCAACAGCCACtt SEQ ID NO: 1108CCCCAACAGCCACAUCCUCtt SEQ ID NO: 1109 CAGCCACAUCCUCCUAUACtt SEQ ID NO:1110 GUGGUGGUGGGGGUAGUCAtt SEQ ID NO: 1111 GGAAAAAUAACUGGACAUCtt SEQ IDNO: 1112 AAAUAACUGGACAUCUUUGtt SEQ ID NO: 1113 AUAACUGGACAUCUUUGUGtt SEQID NO: 1114 CUGGACAUCUUUGUGUAAAtt SEQ ID NO: 1115 ACCAUAAUCCACAUGUGCCttSEQ ID NO: 1116 UCCACAUGUGCCGUAAAUGtt SEQ ID NO: 1117AUGAUCUUCACUCCUUAUCtt SEQ ID NO: 1118 AUUCACAAGGAUCCCCAAGtt SEQ ID NO:1119 GGAUCCCCAAGAUCCACUUtt SEQ ID NO: 1120 GAUCCACUUUUAGAAGCCAtt

TABLE 7 Candidate siRNAs for IKZF4, SEQ ID NOs: 1121-1592 are based onNM_022465. SEQ ID NO: 1121 GGCCCAGGACACGGACAGCtt SEQ ID NO: 1122GAGGGAAAGGCAGAUGCUGtt SEQ ID NO: 1123 CUAGGCUACAGCAUCCCUUtt SEQ ID NO:1124 UGCUAGGCUACAGCAUCCCtt SEQ ID NO: 1125 AGAGCACGCUUGGAUGUGCtt SEQ IDNO: 1126 AGGAGAGGGGAGAGCACGCtt SEQ ID NO: 1127 AGCCCAGGGUGUAUGUGUGtt SEQID NO: 1128 UGAGGGGAACCGCCGUCAUtt SEQ ID NO: 1129 ACCUUCCAGGAAGCGUGGAttSEQ ID NO: 1130 GUGAGCCCAGCCACUCACCtt SEQ ID NO: 1131UGCGAACGCGGCCGCCGCCtt SEQ ID NO: 1132 UCUCCAGAUUAUCCUUCCCtt SEQ ID NO:1133 AUCCCUCUCCAGAUUAUCCtt SEQ ID NO: 1134 UGAGGGAUCCCUCUCCAGAtt SEQ IDNO: 1135 UUAUAAAAUGGUUGGAGUCtt SEQ ID NO: 1136 AGAUUCCAUUAUAAAAUGGtt SEQID NO: 1137 UCACAAAAUAAAGAUUCCAtt SEQ ID NO: 1138 UACUUUCACAAAAUAAAGAttSEQ ID NO: 1139 GAGAUGAGUCCCCGCUACUtt SEQ ID NO: 1140UGGGGCCCCGAGGAACUCCtt SEQ ID NO: 1141 AGGAGAAGAGUGCUGGCUGtt SEQ ID NO:1142 CAUCUCCACCUUGAUGGAGtt SEQ ID NO: 1143 AUCGCUGUACAUCUCCACCtt SEQ IDNO: 1144 UCUGGCCCCAGCAGUCUGCtt SEQ ID NO: 1145 CAAUCACGCUGUCGUCCUUtt SEQID NO: 1146 CACAAUCACGCUGUCGUCCtt SEQ ID NO: 1147 GGGGCUCAGACAAUGAAUCttSEQ ID NO: 1148 GUCACACUUGAGCUUGCCAtt SEQ ID NO: 1149GCAGACGUCACACUUGAGCtt SEQ ID NO: 1150 CAUGCCGCAGACGUCACACtt SEQ ID NO:1151 CUUGUGCACCAUGAGCACGtt SEQ ID NO: 1152 UUCACCAGUGUGACUGCGCtt SEQ IDNO: 1153 GGUUGCAAUGGAAGGGCCUtt SEQ ID NO: 1154 GAAGGAGGCACCACACUGGtt SEQID NO: 1155 GUGGCGCAGCAGGUUCCCCtt SEQ ID NO: 1156 CUUGAUGUGGCGCAGCAGGttSEQ ID NO: 1157 CUUCUCCCCAGAGUGCAGCtt SEQ ID NO: 1158GAAGGGACAUUUAAAGGGCtt SEQ ID NO: 1159 AUAGUUGCAGAAGGGACAUtt SEQ ID NO:1160 ACGCCGGCGGCAGGCAUAGtt SEQ ID NO: 1161 GUAGUUACACUUGUAGGGCtt SEQ IDNO: 1162 CCGGCCACAGUAGUUACACtt SEQ ID NO: 1163 GUAGCUCCGGCCACAGUAGtt SEQID NO: 1164 CUCCAGGGUACUCUGCUGUtt SEQ ID NO: 1165 GUAGUUAUGGCACCGCUCCttSEQ ID NO: 1166 GCUGAGACUCUGUAGGUAGtt SEQ ID NO: 1167GGCCAGCCAAAGCUUGGGCtt SEQ ID NO: 1168 CUGGUUGGCCAGCCAAAGCtt SEQ ID NO:1169 CACGUAUUUCGUCACCUGGtt SEQ ID NO: 1170 CCAUCUCCAGGUCACGUAUtt SEQ IDNO: 1171 GCCAGACGAUCGAUGAAAGtt SEQ ID NO: 1172 CUUGCGUUUGGUGAGGCUAtt SEQID NO: 1173 GGGUGUGGAACGCUUGCGUtt SEQ ID NO: 1174 CUUCUGGGGUGUGGAACGCttSEQ ID NO: 1175 CUGCUUUUCGCCUACAAACtt SEQ ID NO: 1176GGCUGAAGCGCAUCUGCUUtt SEQ ID NO: 1177 GAGGCUGAAGCGCAUCUGCtt SEQ ID NO:1178 CUUUUCAUAGCCACCCGAGtt SEQ ID NO: 1179 CCACCAACUCCACAUCCUUtt SEQ IDNO: 1180 UGCCACCAACUCCACAUCCtt SEQ ID NO: 1181 CCCACAAAGGCCAGGGAACtt SEQID NO: 1182 CGUGAGUUCUGAGAUGCAAtt SEQ ID NO: 1183 AGCUGAUGACAGGCGUGAGttSEQ ID NO: 1184 CCUCAGGUCCCUCACCUGCtt SEQ ID NO: 1185UGUGGAGUCCUGGCAGCCAtt SEQ ID NO: 1186 CCCGAUCUUCGUGGUUGCUtt SEQ ID NO:1187 CGCAACCCGAUCUUCGUGGtt SEQ ID NO: 1188 CCACCCCCGCAACCCGAUCtt SEQ IDNO: 1189 CUGUGGCUUGGGGUCCUCUtt SEQ ID NO: 1190 CAAUAACCCCUCCUGUGGCtt SEQID NO: 1191 CACCACCCGAAGCACUUCCtt SEQ ID NO: 1192 CGCCCACCACCCGAAGCACttSEQ ID NO: 1193 GUGCUCACACUUGAAGGCCtt SEQ ID NO: 1194GAUACGGCAGUGCUCACACtt SEQ ID NO: 1195 GCUGUGAUAACCACAGAUGtt SEQ ID NO:1196 GGACAAUGUGGGAAGAGAAtt SEQ ID NO: 1197 GAGAGGUUGCUAGCCCACCtt SEQ IDNO: 1198 CUGAGGAGAGAGGGAGAGGtt SEQ ID NO: 1199 GGCUACAAAGCAAAACUCCtt SEQID NO: 1200 AUCUGUUUCAUCACAAUGCtt SEQ ID NO: 1201 ACAUAAGCAAAAGAUCUGUttSEQ ID NO: 1202 GCAAAAAUAAAUCAACUAAtt SEQ ID NO: 1203GACUGAUAUAAGUUAAAAUtt SEQ ID NO: 1204 GGCAAGUGACUGAUAUAAGtt SEQ ID NO:1205 GGCCUAAAGUGGAAAGGAGtt SEQ ID NO: 1206 AAGAUCUAAGAGAGAAAAAtt SEQ IDNO: 1207 UCUUAGUACUAAGAGGAGCtt SEQ ID NO: 1208 GCAAGAAGCUUGAAGUCUCtt SEQID NO: 1209 AGGACUUAAAGCAAGAAGCtt SEQ ID NO: 1210 UAAUGUAAAGGGUGAGGACttSEQ ID NO: 1211 CAGCAUCAAAACUGAAGAAtt SEQ ID NO: 1212AGAGGUAUGGAGUACCAGGtt SEQ ID NO: 1213 GGAAAUAAUUCUUCAUUCAtt SEQ ID NO:1214 AUGAGGAAAUAAUUCUUCAtt SEQ ID NO: 1215 CCAAAUGAGGAAAUAAUUCtt SEQ IDNO: 1216 CUUCCAAAUGAGGAAAUAAtt SEQ ID NO: 1217 UUUCUUCAGUCCCUCCUACtt SEQID NO: 1218 AGUGCCUGGGGAGAAUUUCtt SEQ ID NO: 1219 CACAGUGCCUGGGGAGAAUttSEQ ID NO: 1220 ACUAGGGGAAUAUGACCUAtt SEQ ID NO: 1221UAGGCUUUGAGAACUCAUAtt SEQ ID NO: 1222 GAGAUCCUGAAUGUAGGCUtt SEQ ID NO:1223 AGAGCGUGUGGAGGGGUAGtt SEQ ID NO: 1224 CACUUAAUAGACCGGUAGGtt SEQ IDNO: 1225 AGGAGAGAAAAGCCACCACtt SEQ ID NO: 1226 GGCCCCUGAGAAUAUAAAAtt SEQID NO: 1227 GAGGGUUGCAGACCUAGCCtt SEQ ID NO: 1228 AUCUGUCAGAGACAGAGGGttSEQ ID NO: 1229 CCCAUGCCCUGGUUCCCAAtt SEQ ID NO: 1230CUCCUUUCCCAUGCCCUGGtt SEQ ID NO: 1231 AGAAUUUUGACCCACUCCUtt SEQ ID NO:1232 GAGGAGAAAGAGAAGAAUUtt SEQ ID NO: 1233 UGGAGGAGAAAGAGAAGAAtt SEQ IDNO: 1234 GUCACUAUAGUGAAGAAGUtt SEQ ID NO: 1235 CAGGCAGCAACCCACUAGUtt SEQID NO: 1236 GAGGGGCUGAAACAACCCCtt SEQ ID NO: 1237 AGAGAAAAGAGAUACCCGUttSEQ ID NO: 1238 UUUUUGGUUAUACUGAAAAtt SEQ ID NO: 1239AUGCUGGGAUAAUUUUUGGtt SEQ ID NO: 1240 GCUCAUGCUGGGAUAAUUUtt SEQ ID NO:1241 GUGCUCAUGCUGGGAUAAUtt SEQ ID NO: 1242 AGUUGUACCCAUCCCAGUCtt SEQ IDNO: 1243 AAGGAAGACCCCAGUUCAGtt SEQ ID NO: 1244 UAGUAAAGGAAGACCCCAGtt SEQID NO: 1245 CCUUCUCACUAAUCCUAGGtt SEQ ID NO: 1246 UUGUAUCUCCUUCUGCCCCttSEQ ID NO: 1247 GCAGUGGAGUUGUAUCUCCtt SEQ ID NO: 1248ACCUCCACUUGCAGUGGAGtt SEQ ID NO: 1249 UGUAGAAAGAAACCUCCACtt SEQ ID NO:1250 GGCCUUGGGCAGAAAACUCtt SEQ ID NO: 1251 GAGUGGGAUGGCUGUGGCCtt SEQ IDNO: 1252 UAGAAAAACAGCCUUUGGUtt SEQ ID NO: 1253 AAACAUAGAAAAACAGCCUtt SEQID NO: 1254 UUUUUACUUUUUUUUUUCUtt SEQ ID NO: 1255 UUGGUUUUUACUUUUUUUUttSEQ ID NO: 1256 GUUUGGUUUUUACUUUUUUtt SEQ ID NO: 1257GUGUUUGGUUUUUACUUUUtt SEQ ID NO: 1258 UUGUGUUUGGUUUUUACUUtt SEQ ID NO:1259 UGUUGUGUUUGGUUUUUACtt SEQ ID NO: 1260 GAGGUGUUGUGUUUGGUUUtt SEQ IDNO: 1261 GUGAGGUGUUGUGUUUGGUtt SEQ ID NO: 1262 AACUUGUGAGGUGUUGUGUtt SEQID NO: 1263 AGUUACAACUUGUGAGGUGtt SEQ ID NO: 1264 AAGGACCAAGAGUUACAACttSEQ ID NO: 1265 GAGAGAGAAGGACCAAGAGtt SEQ ID NO: 1266CUGUUCCUUAGCCCACCCUtt SEQ ID NO: 1267 UAAUCCCAGGGUCUGUUCCtt SEQ ID NO:1268 GCCCUAAUCCCAGGGUCUGtt SEQ ID NO: 1269 UAGACUCCUCUCAGAGCCCtt SEQ IDNO: 1270 AAGUUUUUUAGGGUCUCCCtt SEQ ID NO: 1271 ACAAAGAGGAGAAAGUUUUtt SEQID NO: 1272 GGACAAAGAGGAGAAAGUUtt SEQ ID NO: 1273 GAGGACAAAGAGGAGAAAGttSEQ ID NO: 1274 CCCUGCCAAUCUGGUUCUCtt SEQ ID NO: 1275CUUCUCCCUGCCAAUCUGGtt SEQ ID NO: 1276 AACAAUUGCCCCACAAUGCtt SEQ ID NO:1277 CAUUGUCAAGGAGGAACAAtt SEQ ID NO: 1278 GCAUCUAUUUAUUGCUACAtt SEQ IDNO: 1279 CCUUGGCAGCAUCUAUUUAtt SEQ ID NO: 1280 UGCCCUUGGCAGCAUCUAUtt SEQID NO: 1281 ACCUCCCCAUUUUCUGCCCtt SEQ ID NO: 1282 CUGAGCUAACCUCCCCAUUttSEQ ID NO: 1283 CUCUGAGCUAACCUCCCCAtt SEQ ID NO: 1284GCCGUUGAGGAUUCUUCCUtt SEQ ID NO: 1285 AGGGUGCCGUUGAGGAUUCtt SEQ ID NO:1286 CCCAGGGUGCCGUUGAGGAtt SEQ ID NO: 1287 CUAGCACCCCAGGGUGCCGtt SEQ IDNO: 1288 AAUCUCAGCUCUGCUGACAtt SEQ ID NO: 1289 UUCAGGAAAAGCCCAGAUAtt SEQID NO: 1290 GGCUCAAUAACCAGAAUAGtt SEQ ID NO: 1291 CCCCAGAAGGGACUAGUCCttSEQ ID NO: 1292 GAGGUUACAGGUGCCACAGtt SEQ ID NO: 1293UCCUUCAUGUUCCGGGAGGtt SEQ ID NO: 1294 CAGAGCAUAGUCCUUCAUGtt SEQ ID NO:1295 UAGCCUCAGAGCAUAGUCCtt SEQ ID NO: 1296 UUAGCACCUGGUCUUGCCCtt SEQ IDNO: 1297 CCCUCCUUAGCACCUGGUCtt SEQ ID NO: 1298 GAUGCCCCCUCUCCCCUCCtt SEQID NO: 1299 UUUGUACCUAAGACCCUGGtt SEQ ID NO: 1300 GGCUCUGAAAAGUAGGAUUttSEQ ID NO: 1301 AAGGCUCUGAAAAGUAGGAtt SEQ ID NO: 1302AGCAUGAGGAUGUUUGAGGtt SEQ ID NO: 1303 GGAGAGAGCAUGAGGAUGUtt SEQ ID NO:1304 UUUUUCUUUACUUUUUUUUtt SEQ ID NO: 1305 UCUUUUUCUUUACUUUUUUtt SEQ IDNO: 1306 UUUCUUUUUCUUUACUUUUtt SEQ ID NO: 1307 UUUUUCUUUUUCUUUACUUtt SEQID NO: 1308 UUUUUUUCUUUUUCUUUACtt SEQ ID NO: 1309 UAUUUUUUUUUCUUUUUCUttSEQ ID NO: 1310 UGUGUAUUUUUUUUUCUUUtt SEQ ID NO: 1311UGUGUGUAUUUUUUUUUCUtt SEQ ID NO: 1312 AGUGUGUGUGUAUUUUUUUtt SEQ ID NO:1313 UCAGUGUGUGUGUAUUUUUtt SEQ ID NO: 1314 UUUCAGUGUGUGUGUAUUUtt SEQ IDNO: 1315 GGUUUCAGUGUGUGUGUAUtt SEQ ID NO: 1316 CUCUUUUCUCCAUGUGGGUtt SEQID NO: 1317 AUAAAAGGAAACACCUCUUtt SEQ ID NO: 1318 AUAUAAAAGGAAACACCUCttSEQ ID NO: 1319 UUUGUUGGUGGUAUUGAUUtt SEQ ID NO: 1320AUUUUGUUGGUGGUAUUGAtt SEQ ID NO: 1321 AAAUAUUUUGUUGGUGGUAtt SEQ ID NO:1322 UCUACUUAGAAAUAUUUUGtt SEQ ID NO: 1323 GUGUCUACUUAGAAAUAUUtt SEQ IDNO: 1324 AAGUGUCUACUUAGAAAUAtt SEQ ID NO: 1325 GGUCUGGAAAAGUGUCUACtt SEQID NO: 1326 ACAAAAUCCUAUCUGCAGCtt SEQ ID NO: 1327 AAAGAAGCUGCCAGAAGUAttSEQ ID NO: 1328 AUAUAUGUAUAUAUAUAUAtt SEQ ID NO: 1329UGUUCUUCAUAACUUCUGAtt SEQ ID NO: 1330 UCUUUUUGUUCUUCAUAACtt SEQ ID NO:1331 UUAUUUUUUCUUUUUGUUCtt SEQ ID NO: 1332 UGUUUAUUUUUUCUUUUUGtt SEQ IDNO: 1333 CUGUGUUUAUUUUUUCUUUtt SEQ ID NO: 1334 UUCUGUGUUUAUUUUUUCUtt SEQID NO: 1335 UUGCUUCUGUGUUUAUUUUtt SEQ ID NO: 1336 ACUUGCUUCUGUGUUUAUUttSEQ ID NO: 1337 GCACUUGCUUCUGUGUUUAtt SEQ ID NO: 1338AUUGCACUUGCUUCUGUGUtt SEQ ID NO: 1339 GAGGUGGUAUUGCACUUGCtt SEQ ID NO:1340 AAGAGAGGUGGUAUUGCACtt SEQ ID NO: 1341 AGGGAGAAGAGAGGUGGUAtt SEQ IDNO: 1342 GAGAAAGGAGAAAAACUCUtt SEQ ID NO: 1343 AAAGCUAGUUUAACUCCCCtt SEQID NO: 1344 AUAAGUCUCAAAAGCUAGUtt SEQ ID NO: 1345 AUUACAUAUACAAAAUGCUttSEQ ID NO: 1346 AAUAUUUACUUACAAUAUAtt SEQ ID NO: 1347CCGUUACACAAAUAUUUACtt SEQ ID NO: 1348 AUCUCCGUUACACAAAUAUtt SEQ ID NO:1349 UUACAGUAGUAUAUCUCCGtt SEQ ID NO: 1350 AGCCAGUACAGUACAAAACtt SEQ IDNO: 1351 UGUUUAUUUAUAACAGACUtt SEQ ID NO: 1352 UUAAAUUACUCAUGUUUAUtt SEQID NO: 1353 GGUGUUAAAUUACUCAUGUtt SEQ ID NO: 1354 UUUUUUUUUUGGUGUUAAAttSEQ ID NO: 1355 UUUUUUUUUUUUUUUGGUGtt SEQ ID NO: 1356UUUUUUUUUUUUUUUUUUUtt SEQ ID NO: 1357 GCUGUCCGUGUCCUGGGCCtt SEQ ID NO:1358 CAGCAUCUGCCUUUCCCUCtt SEQ ID NO: 1359 AAGGGAUGCUGUAGCCUAGtt SEQ IDNO: 1360 GGGAUGCUGUAGCCUAGCAtt SEQ ID NO: 1361 GCACAUCCAAGCGUGCUCUtt SEQID NO: 1362 GCGUGCUCUCCCCUCUCCUtt SEQ ID NO: 1363 CACACAUACACCCUGGGCUttSEQ ID NO: 1364 AUGACGGCGGUUCCCCUCAtt SEQ ID NO: 1365UCCACGCUUCCUGGAAGGUtt SEQ ID NO: 1366 GGUGAGUGGCUGGGCUCACtt SEQ ID NO:1367 GGCGGCGGCCGCGUUCGCAtt SEQ ID NO: 1368 GGGAAGGAUAAUCUGGAGAtt SEQ IDNO: 1369 GGAUAAUCUGGAGAGGGAUtt SEQ ID NO: 1370 UCUGGAGAGGGAUCCCUCAtt SEQID NO: 1371 GACUCCAACCAUUUUAUAAtt SEQ ID NO: 1372 CCAUUUUAUAAUGGAAUCUttSEQ ID NO: 1373 UGGAAUCUUUAUUUUGUGAtt SEQ ID NO: 1374UCUUUAUUUUGUGAAAGUAtt SEQ ID NO: 1375 AGUAGCGGGGACUCAUCUCtt SEQ ID NO:1376 GGAGUUCCUCGGGGCCCCAtt SEQ ID NO: 1377 CAGCCAGCACUCUUCUCCUtt SEQ IDNO: 1378 CUCCAUCAAGGUGGAGAUGtt SEQ ID NO: 1379 GGUGGAGAUGUACAGCGAUtt SEQID NO: 1380 GCAGACUGCUGGGGCCAGAtt SEQ ID NO: 1381 AAGGACGACAGCGUGAUUGttSEQ ID NO: 1382 GGACGACAGCGUGAUUGUGtt SEQ ID NO: 1383GAUUCAUUGUCUGAGCCCCtt SEQ ID NO: 1384 UGGCAAGCUCAAGUGUGACtt SEQ ID NO:1385 GCUCAAGUGUGACGUCUGCtt SEQ ID NO: 1386 GUGUGACGUCUGCGGCAUGtt SEQ IDNO: 1387 CGUGCUCAUGGUGCACAAGtt SEQ ID NO: 1388 GCGCAGUCACACUGGUGAAtt SEQID NO: 1389 AGGCCCUUCCAUUGCAACCtt SEQ ID NO: 1390 CCAGUGUGGUGCCUCCUUCttSEQ ID NO: 1391 GGGGAACCUGCUGCGCCACtt SEQ ID NO: 1392CCUGCUGCGCCACAUCAAGtt SEQ ID NO: 1393 GCUGCACUCUGGGGAGAAGtt SEQ ID NO:1394 GCCCUUUAAAUGUCCCUUCtt SEQ ID NO: 1395 AUGUCCCUUCUGCAACUAUtt SEQ IDNO: 1396 CUAUGCCUGCCGCCGGCGUtt SEQ ID NO: 1397 GCCCUACAAGUGUAACUACtt SEQID NO: 1398 GUGUAACUACUGUGGCCGGtt SEQ ID NO: 1399 CUACUGUGGCCGGAGCUACttSEQ ID NO: 1400 ACAGCAGAGUACCCUGGAGtt SEQ ID NO: 1401GGAGCGGUGCCAUAACUACtt SEQ ID NO: 1402 CUACCUACAGAGUCUCAGCtt SEQ ID NO:1403 GCCCAAGCUUUGGCUGGCCtt SEQ ID NO: 1404 GCUUUGGCUGGCCAACCAGtt SEQ IDNO: 1405 CCAGGUGACGAAAUACGUGtt SEQ ID NO: 1406 AUACGUGACCUGGAGAUGGtt SEQID NO: 1407 CUUUCAUCGAUCGUCUGGCtt SEQ ID NO: 1408 UAGCCUCACCAAACGCAAGttSEQ ID NO: 1409 ACGCAAGCGUUCCACACCCtt SEQ ID NO: 1410GCGUUCCACACCCCAGAAGtt SEQ ID NO: 1411 GUUUGUAGGCGAAAAGCAGtt SEQ ID NO:1412 AAGCAGAUGCGCUUCAGCCtt SEQ ID NO: 1413 GCAGAUGCGCUUCAGCCUCtt SEQ IDNO: 1414 CUCGGGUGGCUAUGAAAAGtt SEQ ID NO: 1415 AAGGAUGUGGAGUUGGUGGtt SEQID NO: 1416 GGAUGUGGAGUUGGUGGCAtt SEQ ID NO: 1417 GUUCCCUGGCCUUUGUGGGttSEQ ID NO: 1418 UUGCAUCUCAGAACUCACGtt SEQ ID NO: 1419CUCACGCCUGUCAUCAGCUtt SEQ ID NO: 1420 GCAGGUGAGGGACCUGAGGtt SEQ ID NO:1421 UGGCUGCCAGGACUCCACAtt SEQ ID NO: 1422 AGCAACCACGAAGAUCGGGtt SEQ IDNO: 1423 CCACGAAGAUCGGGUUGCGtt SEQ ID NO: 1424 GAUCGGGUUGCGGGGGUGGtt SEQID NO: 1425 AGAGGACCCCAAGCCACAGtt SEQ ID NO: 1426 GCCACAGGAGGGGUUAUUGttSEQ ID NO: 1427 GGAAGUGCUUCGGGUGGUGtt SEQ ID NO: 1428GUGCUUCGGGUGGUGGGCGtt SEQ ID NO: 1429 GGCCUUCAAGUGUGAGCACtt SEQ ID NO:1430 GUGUGAGCACUGCCGUAUCtt SEQ ID NO: 1431 CAUCUGUGGUUAUCACAGCtt SEQ IDNO: 1432 UUCUCUUCCCACAUUGUCCtt SEQ ID NO: 1433 GGUGGGCUAGCAACCUCUCtt SEQID NO: 1434 CCUCUCCCUCUCUCCUCAGtt SEQ ID NO: 1435 GGAGUUUUGCUUUGUAGCCttSEQ ID NO: 1436 GCAUUGUGAUGAAACAGAUtt SEQ ID NO: 1437ACAGAUCUUUUGCUUAUGUtt SEQ ID NO: 1438 UUAGUUGAUUUAUUUUUGCtt SEQ ID NO:1439 AUUUUAACUUAUAUCAGUCtt SEQ ID NO: 1440 CUUAUAUCAGUCACUUGCCtt SEQ IDNO: 1441 CUCCUUUCCACUUUAGGCCtt SEQ ID NO: 1442 UUUUUCUCUCUUAGAUCUUtt SEQID NO: 1443 GCUCCUCUUAGUACUAAGAtt SEQ ID NO: 1444 GAGACUUCAAGCUUCUUGCttSEQ ID NO: 1445 GCUUCUUGCUUUAAGUCCUtt SEQ ID NO: 1446GUCCUCACCCUUUACAUUAtt SEQ ID NO: 1447 UUCUUCAGUUUUGAUGCUGtt SEQ ID NO:1448 CCUGGUACUCCAUACCUCUtt SEQ ID NO: 1449 UGAAUGAAGAAUUAUUUCCtt SEQ IDNO: 1450 UGAAGAAUUAUUUCCUCAUtt SEQ ID NO: 1451 GAAUUAUUUCCUCAUUUGGtt SEQID NO: 1452 UUAUUUCCUCAUUUGGAAGtt SEQ ID NO: 1453 GUAGGAGGGACUGAAGAAAttSEQ ID NO: 1454 GAAAUUCUCCCCAGGCACUtt SEQ ID NO: 1455AUUCUCCCCAGGCACUGUGtt SEQ ID NO: 1456 UAGGUCAUAUUCCCCUAGUtt SEQ ID NO:1457 UAUGAGUUCUCAAAGCCUAtt SEQ ID NO: 1458 AGCCUACAUUCAGGAUCUCtt SEQ IDNO: 1459 CUACCCCUCCACACGCUCUtt SEQ ID NO: 1460 CCUACCGGUCUAUUAAGUGtt SEQID NO: 1461 GUGGUGGCUUUUCUCUCCUtt SEQ ID NO: 1462 UUUUAUAUUCUCAGGGGCCttSEQ ID NO: 1463 GGCUAGGUCUGCAACCCUCtt SEQ ID NO: 1464CCCUCUGUCUCUGACAGAUtt SEQ ID NO: 1465 UUGGGAACCAGGGCAUGGGtt SEQ ID NO:1466 CCAGGGCAUGGGAAAGGAGtt SEQ ID NO: 1467 AGGAGUGGGUCAAAAUUCUtt SEQ IDNO: 1468 AAUUCUUCUCUUUCUCCUCtt SEQ ID NO: 1469 UUCUUCUCUUUCUCCUCCAtt SEQID NO: 1470 ACUUCUUCACUAUAGUGACtt SEQ ID NO: 1471 ACUAGUGGGUUGCUGCCUGttSEQ ID NO: 1472 GGGGUUGUUUCAGCCCCUCtt SEQ ID NO: 1473ACGGGUAUCUCUUUUCUCUtt SEQ ID NO: 1474 UUUUCAGUAUAACCAAAAAtt SEQ ID NO:1475 CCAAAAAUUAUCCCAGCAUtt SEQ ID NO: 1476 AAAUUAUCCCAGCAUGAGCtt SEQ IDNO: 1477 AUUAUCCCAGCAUGAGCACtt SEQ ID NO: 1478 GACUGGGAUGGGUACAACUtt SEQID NO: 1479 CUGAACUGGGGUCUUCCUUtt SEQ ID NO: 1480 CUGGGGUCUUCCUUUACUAttSEQ ID NO: 1481 CCUAGGAUUAGUGAGAAGGtt SEQ ID NO: 1482GGGGCAGAAGGAGAUACAAtt SEQ ID NO: 1483 GGAGAUACAACUCCACUGCtt SEQ ID NO:1484 CUCCACUGCAAGUGGAGGUtt SEQ ID NO: 1485 GUGGAGGUUUCUUUCUACAtt SEQ IDNO: 1486 GAGUUUUCUGCCCAAGGCCtt SEQ ID NO: 1487 GGCCACAGCCAUCCCACUCtt SEQID NO: 1488 ACCAAAGGCUGUUUUUCUAtt SEQ ID NO: 1489 AGGCUGUUUUUCUAUGUUUttSEQ ID NO: 1490 AGAAAAAAAAAAGUAAAAAtt SEQ ID NO: 1491AAAAAAAAGUAAAAACCAAtt SEQ ID NO: 1492 AAAAAAGUAAAAACCAAACtt SEQ ID NO:1493 AAAAGUAAAAACCAAACACtt SEQ ID NO: 1494 AAGUAAAAACCAAACACAAtt SEQ IDNO: 1495 GUAAAAACCAAACACAACAtt SEQ ID NO: 1496 AAACCAAACACAACACCUCtt SEQID NO: 1497 ACCAAACACAACACCUCACtt SEQ ID NO: 1498 ACACAACACCUCACAAGUUttSEQ ID NO: 1499 CACCUCACAAGUUGUAACUtt SEQ ID NO: 1500GUUGUAACUCUUGGUCCUUtt SEQ ID NO: 1501 CUCUUGGUCCUUCUCUCUCtt SEQ ID NO:1502 AGGGUGGGCUAAGGAACAGtt SEQ ID NO: 1503 GGAACAGACCCUGGGAUUAtt SEQ IDNO: 1504 CAGACCCUGGGAUUAGGGCtt SEQ ID NO: 1505 GGGCUCUGAGAGGAGUCUAtt SEQID NO: 1506 GGGAGACCCUAAAAAACUUtt SEQ ID NO: 1507 AAAACUUUCUCCUCUUUGUttSEQ ID NO: 1508 AACUUUCUCCUCUUUGUCCtt SEQ ID NO: 1509CUUUCUCCUCUUUGUCCUCtt SEQ ID NO: 1510 GAGAACCAGAUUGGCAGGGtt SEQ ID NO:1511 CCAGAUUGGCAGGGAGAAGtt SEQ ID NO: 1512 GCAUUGUGGGGCAAUUGUUtt SEQ IDNO: 1513 UUGUUCCUCCUUGACAAUGtt SEQ ID NO: 1514 UGUAGCAAUAAAUAGAUGCtt SEQID NO: 1515 UAAAUAGAUGCUGCCAAGGtt SEQ ID NO: 1516 AUAGAUGCUGCCAAGGGCAttSEQ ID NO: 1517 GGGCAGAAAAUGGGGAGGUtt SEQ ID NO: 1518AAUGGGGAGGUUAGCUCAGtt SEQ ID NO: 1519 UGGGGAGGUUAGCUCAGAGtt SEQ ID NO:1520 AGGAAGAAUCCUCAACGGCtt SEQ ID NO: 1521 GAAUCCUCAACGGCACCCUtt SEQ IDNO: 1522 UCCUCAACGGCACCCUGGGtt SEQ ID NO: 1523 CGGCACCCUGGGGUGCUAGtt SEQID NO: 1524 UGUCAGCAGAGCUGAGAUUtt SEQ ID NO: 1525 UAUCUGGGCUUUUCCUGAAttSEQ ID NO: 1526 CUAUUCUGGUUAUUGAGCCtt SEQ ID NO: 1527GGACUAGUCCCUUCUGGGGtt SEQ ID NO: 1528 CUGUGGCACCUGUAACCUCtt SEQ ID NO:1529 CCUCCCGGAACAUGAAGGAtt SEQ ID NO: 1530 CAUGAAGGACUAUGCUCUGtt SEQ IDNO: 1531 GGACUAUGCUCUGAGGCUAtt SEQ ID NO: 1532 GGGCAAGACCAGGUGCUAAtt SEQID NO: 1533 GACCAGGUGCUAAGGAGGGtt SEQ ID NO: 1534 GGAGGGGAGAGGGGGCAUCttSEQ ID NO: 1535 CCAGGGUCUUAGGUACAAAtt SEQ ID NO: 1536AAUCCUACUUUUCAGAGCCtt SEQ ID NO: 1537 UCCUACUUUUCAGAGCCUUtt SEQ ID NO:1538 CCUCAAACAUCCUCAUGCUtt SEQ ID NO: 1539 ACAUCCUCAUGCUCUCUCCtt SEQ IDNO: 1540 AAAAAAAAGUAAAGAAAAAtt SEQ ID NO: 1541 AAAAAAGUAAAGAAAAAGAtt SEQID NO: 1542 AAAAGUAAAGAAAAAGAAAtt SEQ ID NO: 1543 AAGUAAAGAAAAAGAAAAAttSEQ ID NO: 1544 GUAAAGAAAAAGAAAAAAAtt SEQ ID NO: 1545AGAAAAAGAAAAAAAAAUAtt SEQ ID NO: 1546 AAAGAAAAAAAAAUACACAtt SEQ ID NO:1547 AGAAAAAAAAAUACACACAtt SEQ ID NO: 1548 AAAAAAAUACACACACACUtt SEQ IDNO: 1549 AAAAAUACACACACACUGAtt SEQ ID NO: 1550 AAAUACACACACACUGAAAtt SEQID NO: 1551 AUACACACACACUGAAACCtt SEQ ID NO: 1552 ACCCACAUGGAGAAAAGAGttSEQ ID NO: 1553 AAGAGGUGUUUCCUUUUAUtt SEQ ID NO: 1554GAGGUGUUUCCUUUUAUAUtt SEQ ID NO: 1555 AAUCAAUACCACCAACAAAtt SEQ ID NO:1556 UCAAUACCACCAACAAAAUtt SEQ ID NO: 1557 UACCACCAACAAAAUAUUUtt SEQ IDNO: 1558 CAAAAUAUUUCUAAGUAGAtt SEQ ID NO: 1559 AAUAUUUCUAAGUAGACACtt SEQID NO: 1560 UAUUUCUAAGUAGACACUUtt SEQ ID NO: 1561 GUAGACACUUUUCCAGACCttSEQ ID NO: 1562 GCUGCAGAUAGGAUUUUGUtt SEQ ID NO: 1563UACUUCUGGCAGCUUCUUUtt SEQ ID NO: 1564 UAUAUAUAUAUACAUAUAUtt SEQ ID NO:1565 UCAGAAGUUAUGAAGAACAtt SEQ ID NO: 1566 GUUAUGAAGAACAAAAAGAtt SEQ IDNO: 1567 GAACAAAAAGAAAAAAUAAtt SEQ ID NO: 1568 CAAAAAGAAAAAAUAAACAtt SEQID NO: 1569 AAAGAAAAAAUAAACACAGtt SEQ ID NO: 1570 AGAAAAAAUAAACACAGAAttSEQ ID NO: 1571 AAAAUAAACACAGAAGCAAtt SEQ ID NO: 1572AAUAAACACAGAAGCAAGUtt SEQ ID NO: 1573 UAAACACAGAAGCAAGUGCtt SEQ ID NO:1574 ACACAGAAGCAAGUGCAAUtt SEQ ID NO: 1575 GCAAGUGCAAUACCACCUCtt SEQ IDNO: 1576 GUGCAAUACCACCUCUCUUtt SEQ ID NO: 1577 UACCACCUCUCUUCUCCCUtt SEQID NO: 1578 AGAGUUUUUCUCCUUUCUCtt SEQ ID NO: 1579 GGGGAGUUAAACUAGCUUUttSEQ ID NO: 1580 ACUAGCUUUUGAGACUUAUtt SEQ ID NO: 1581AGCAUUUUGUAUAUGUAAUtt SEQ ID NO: 1582 UAUAUUGUAAGUAAAUAUUtt SEQ ID NO:1583 GUAAAUAUUUGUGUAACGGtt SEQ ID NO: 1584 AUAUUUGUGUAACGGAGAUtt SEQ IDNO: 1585 CGGAGAUAUACUACUGUAAtt SEQ ID NO: 1586 GUUUUGUACUGUACUGGCUtt SEQID NO: 1587 AGUCUGUUAUAAAUAAACAtt SEQ ID NO: 1588 AUAAACAUGAGUAAUUUAAttSEQ ID NO: 1589 ACAUGAGUAAUUUAACACCtt SEQ ID NO: 1590UUUAACACCAAAAAAAAAAtt SEQ ID NO: 1591 CACCAAAAAAAAAAAAAAAtt SEQ ID NO:1592 AAAAAAAAAAAAAAAAAAAtt

TABLE 8 Candidate siRNAs for RAB5B, SEQ ID NOs: 1593-1912 are based onNM_002868. SEQ ID NO: 1593 GGGGAGGGGAUUUCCAGGCtt SEQ ID NO: 1594AGGGGGAAGGGGAGGGGAUtt SEQ ID NO: 1595 UCUGCUAGUCAUGGCCAGAtt SEQ ID NO:1596 CCAUUGGGCCUAGCUGUGCtt SEQ ID NO: 1597 GCUGGCCUGGGGUUGCCCAtt SEQ IDNO: 1598 AAAUUUUGCUGGCCUGGGGtt SEQ ID NO: 1599 CAAUUUGAACUGGCAAAUUtt SEQID NO: 1600 ACCAAUUUGAACUGGCAAAtt SEQ ID NO: 1601 UUCUCCCAGCAGGACCAAUttSEQ ID NO: 1602 UUGACUUUCCCACUGCAGAtt SEQ ID NO: 1603CGUAAUACCAGGCUUGACUtt SEQ ID NO: 1604 ACAAAACGUAAUACCAGGCtt SEQ ID NO:1605 GUACUCAUGGAACUGCCCUtt SEQ ID NO: 1606 CAGAUCUCAAACUUCACUGtt SEQ IDNO: 1607 UGUGUCCCAGAUCUCAAACtt SEQ ID NO: 1608 CGUAAACCACGAUUGCAGCtt SEQID NO: 1609 GUAAUGUCGUAAACCACGAtt SEQ ID NO: 1610 UCGGGCAAAGGUUUCCUGAttSEQ ID NO: 1611 UCUUUGCUCGGGCAAAGGUtt SEQ ID NO: 1612AGUUCCUUCACCCAUGUCUtt SEQ ID NO: 1613 GGCCUGUCGCUGUAGUUCCtt SEQ ID NO:1614 GACUGGCCUGUCGCUGUAGtt SEQ ID NO: 1615 GUUGGCCAGGUCAGCUUUGtt SEQ IDNO: 1616 UUUGUUGGCCAGGUCAGCUtt SEQ ID NO: 1617 AUACUCCACCAUACGUUUGtt SEQID NO: 1618 UUCAUACUCCACCAUACGUtt SEQ ID NO: 1619 CUGCAUAUGCCUGGGCCUCttSEQ ID NO: 1620 CUCCAUGAACAAUAAGCUGtt SEQ ID NO: 1621AUUCACGUUCAUAGCUGUCtt SEQ ID NO: 1622 CAGGAAGAGAUCAUUCACGtt SEQ ID NO:1623 UAUUGCCAGGAAGAGAUCAtt SEQ ID NO: 1624 UUUGGCAACUUCUUAGCUAtt SEQ IDNO: 1625 UUCACUCUUUGGCAACUUCtt SEQ ID NO: 1626 GGGUUCACUCUUUGGCAACtt SEQID NO: 1627 AGAUUCUGGGGUUCACUCUtt SEQ ID NO: 1628 CACCUCCCAGAUUCUGGGGttSEQ ID NO: 1629 GCCUGCUGCACCUCCCAGAtt SEQ ID NO: 1630UGGAGAUCCACACCCCGGCtt SEQ ID NO: 1631 UCUUGUUCUGCUGGGACUGtt SEQ ID NO:1632 GCUACAACACUGGCUCUUGtt SEQ ID NO: 1633 GUUGCUACAACACUGGCUCtt SEQ IDNO: 1634 CUGCUAGCCACCCCCUCAGtt SEQ ID NO: 1635 GUGCUAGCUCCAUACUUGUtt SEQID NO: 1636 UCUUGUGCUAGCUCCAUACtt SEQ ID NO: 1637 GGAGGUUAUUUCUUAGCUCttSEQ ID NO: 1638 UAGGGAUGGAGGUUAUUUCtt SEQ ID NO: 1639GGGUAGGGAUGGAGGUUAUtt SEQ ID NO: 1640 UGAGGGGUAGGGAUGGAGGtt SEQ ID NO:1641 UGUGCUGUUACCGUAGGGGtt SEQ ID NO: 1642 GCCAGGGCUCAGUGUGCUGtt SEQ IDNO: 1643 AGCUGUCAGGAGGCAGCCCtt SEQ ID NO: 1644 GGUGUUUGUUGCUGAAGCGtt SEQID NO: 1645 AACAGCUGCCUGGUGUUUGtt SEQ ID NO: 1646 GGCAACAGCUGCCUGGUGUttSEQ ID NO: 1647 AGGUAAGUCCUGGGGGGAGtt SEQ ID NO: 1648AAAGUGAAGAAAGUUUGUUtt SEQ ID NO: 1649 ACAAAGUGAAGAAAGUUUGtt SEQ ID NO:1650 AAUACAAAGUGAAGAAAGUtt SEQ ID NO: 1651 AGAUACGUAAGUCGCUGUCtt SEQ IDNO: 1652 GACAGGAGUCAGAAGUGUUtt SEQ ID NO: 1653 GGGACAGGAGUCAGAAGUGtt SEQID NO: 1654 AGUUCCUGGGUUCACCACUtt SEQ ID NO: 1655 UCCUUCCUCAGUUCCUGGGttSEQ ID NO: 1656 UGGAAACCUCCUUCCUCAGtt SEQ ID NO: 1657AAAUGAACUGGAAACCUCCtt SEQ ID NO: 1658 UUAUUCUCCCCCAGGGCCCtt SEQ ID NO:1659 CCUCCUGCUCUGAGCUUUAtt SEQ ID NO: 1660 CUCCCUCCUGCUCUGAGCUtt SEQ IDNO: 1661 ACAAAAAGGAAAUGUUUCCtt SEQ ID NO: 1662 AAAAACAAAAAGGAAAUGUtt SEQID NO: 1663 UCAUGGAUACCGCAAUGUUtt SEQ ID NO: 1664 AAUCAUGGAUACCGCAAUGttSEQ ID NO: 1665 CUGAGAUCUUGCCUCCCCAtt SEQ ID NO: 1666CUGCCUGGUGCCUGAGAUCtt SEQ ID NO: 1667 CCACCUCCGCCCAGUUAGCtt SEQ ID NO:1668 CACCUCCACCUCCGCCCAGtt SEQ ID NO: 1669 AAGAGUUACAGAGCCACAGtt SEQ IDNO: 1670 AAACUGGGCCUUUGAAGAGtt SEQ ID NO: 1671 GUGAGGGGAAACUGGGCCUtt SEQID NO: 1672 UGGGGUCCAACCCCCACGAtt SEQ ID NO: 1673 GGCAACCAGUGAAAAUUCUttSEQ ID NO: 1674 UGCAGGCAACCAGUGAAAAtt SEQ ID NO: 1675CCAACUGAACUACCAUCAAtt SEQ ID NO: 1676 CAAGUAAAUCAAUCAAAACtt SEQ ID NO:1677 AACCUCAGAUUUCAUUGAAtt SEQ ID NO: 1678 GCAUUAACCUCAGAUUUCAtt SEQ IDNO: 1679 CCUCGCAUUAACCUCAGAUtt SEQ ID NO: 1680 CCUCUCCUCGAACCUCGCAtt SEQID NO: 1681 GUAGCUGCCACUGGUAGUUtt SEQ ID NO: 1682 GAGUAGCUGCCACUGGUAGttSEQ ID NO: 1683 CUAACAGUGGAGAUAGGACtt SEQ ID NO: 1684UAUAGGUUAAUAAUUAGAGtt SEQ ID NO: 1685 CAAGAAUAUAGGUUAAUAAtt SEQ ID NO:1686 AGCUUGGCAAGAAUAUAGGtt SEQ ID NO: 1687 CCUAUAGUCAAUAGUUAGCtt SEQ IDNO: 1688 GCAAACCUAUAGUCAAUAGtt SEQ ID NO: 1689 UCCUCAAUUGCUCAAUUAAtt SEQID NO: 1690 ACACUCCUCAAUUGCUCAAtt SEQ ID NO: 1691 AUCCUGAGACACUCCUCAAttSEQ ID NO: 1692 UCCUUUUUACUCCCCUACCtt SEQ ID NO: 1693CUUUUGCCUGACCUCCUUUtt SEQ ID NO: 1694 CCCUUUUGCCUGACCUCCUtt SEQ ID NO:1695 GACAGAAAACUCCUCCCUUtt SEQ ID NO: 1696 AGGACAGAAAACUCCUCCCtt SEQ IDNO: 1697 CAUGGUAAUGGAUAUCAAAtt SEQ ID NO: 1698 GAAUAAAGAUCAUACCUAUtt SEQID NO: 1699 AGGGACUAAAUUCAAGAUAtt SEQ ID NO: 1700 UAAGGAUGGAGGGACUAAAttSEQ ID NO: 1701 AUGGGGAGGGAUGGGGGGAtt SEQ ID NO: 1702ACAUGGAUUAAACCACUGGtt SEQ ID NO: 1703 GCCCCUAUUGGUACAUGGAtt SEQ ID NO:1704 UCUGUGGUACUAGCCCCUAtt SEQ ID NO: 1705 GUACCUUCAGUGCCGGUCAtt SEQ IDNO: 1706 GAGCCAGUUGUAAGGUACCtt SEQ ID NO: 1707 CUCUGAUAAUAUGAGCCAGtt SEQID NO: 1708 AUGAAGAGAGACUAGAGAUtt SEQ ID NO: 1709 AUGGCUUCUCAGAGACAUCttSEQ ID NO: 1710 UCUCUUUUGCCUUGAUGGCtt SEQ ID NO: 1711CUUAAAGUUCUCUUUUGCCtt SEQ ID NO: 1712 AGGAACUUAAAGUUCUCUUtt SEQ ID NO:1713 CAAGGAACUUAAAGUUCUCtt SEQ ID NO: 1714 UGGAACAAGGAACUUAAAGtt SEQ IDNO: 1715 CCGGGCUGGAACAAGGAACtt SEQ ID NO: 1716 UGACCUUUCCUUUCUUUCUtt SEQID NO: 1717 ACUGUGACCUUUCCUUUCUtt SEQ ID NO: 1718 GGUCACUGUGACCUUUCCUttSEQ ID NO: 1719 UCCUAGGUCACUGUGACCUtt SEQ ID NO: 1720AGCCAAAAGGGCAGGAAGGtt SEQ ID NO: 1721 UUCAUAGAUUUCUCAGCUGtt SEQ ID NO:1722 GAAUCUCAGCUUCAUAGAUtt SEQ ID NO: 1723 GGUCCUUCAGAAUCUCAGCtt SEQ IDNO: 1724 AAGAACCUAAGCUGGGUCCtt SEQ ID NO: 1725 CCCUGGAAAAGGAAGGGAAtt SEQID NO: 1726 AAGGGGGAAAUGUGUGUGUtt SEQ ID NO: 1727 GCUAUGGGGGGCCAGUGGCttSEQ ID NO: 1728 GCCAUCCUAGUUCUUCCACtt SEQ ID NO: 1729UGGAAAGCCAUCCUAGUUCtt SEQ ID NO: 1730 CUUUGGAAAGCCAUCCUAGtt SEQ ID NO:1731 ACUUCAUUUCUAGAAGACUtt SEQ ID NO: 1732 CACAGAGAAAGAACUUCAUtt SEQ IDNO: 1733 AGCUGCACAGAGAAAGAACtt SEQ ID NO: 1734 CCCAAGAUAAUGAAACAUCtt SEQID NO: 1735 AGAAGCCUGGGGAAGUGGUtt SEQ ID NO: 1736 AAGCUAAGGCCAAAUCCUGttSEQ ID NO: 1737 AAAACCACAACACCCCCCCtt SEQ ID NO: 1738AGGAAGAAAGGCAAAUGCUtt SEQ ID NO: 1739 UGUUACCACGAUUGUUAUGtt SEQ ID NO:1740 CAUUCUGUUACCACGAUUGtt SEQ ID NO: 1741 UCGCAUUCUGUUACCACGAtt SEQ IDNO: 1742 AAUCAGCAGUCGCAUUCUGtt SEQ ID NO: 1743 CGGUAAAUCAGCAGUCGCAtt SEQID NO: 1744 UUUCCUUUUUUUACUUACAtt SEQ ID NO: 1745 CUUUUUUUCCUUUUUUUACttSEQ ID NO: 1746 UUUUCUUUUUUUCCUUUUUtt SEQ ID NO: 1747UUUUUUCUUUUUUUCCUUUtt SEQ ID NO: 1748 UUUUUUUUCUUUUUUUCCUtt SEQ ID NO:1749 UUUUUUUUUUUUUCUUUUUtt SEQ ID NO: 1750 UUUUUUUUUUUUUUUCUUUtt SEQ IDNO: 1751 UUUUUUUUUUUUUUUUUCUtt SEQ ID NO: 1752 UUUUUUUUUUUUUUUUUUUtt SEQID NO: 1753 GCCUGGAAAUCCCCUCCCCtt SEQ ID NO: 1754 AUCCCCUCCCCUUCCCCCUttSEQ ID NO: 1755 UCUGGCCAUGACUAGCAGAtt SEQ ID NO: 1756GCACAGCUAGGCCCAAUGGtt SEQ ID NO: 1757 UGGGCAACCCCAGGCCAGCtt SEQ ID NO:1758 CCCCAGGCCAGCAAAAUUUtt SEQ ID NO: 1759 AAUUUGCCAGUUCAAAUUGtt SEQ IDNO: 1760 UUUGCCAGUUCAAAUUGGUtt SEQ ID NO: 1761 AUUGGUCCUGCUGGGAGAAtt SEQID NO: 1762 UCUGCAGUGGGAAAGUCAAtt SEQ ID NO: 1763 AGUCAAGCCUGGUAUUACGttSEQ ID NO: 1764 GCCUGGUAUUACGUUUUGUtt SEQ ID NO: 1765AGGGCAGUUCCAUGAGUACtt SEQ ID NO: 1766 CAGUGAAGUUUGAGAUCUGtt SEQ ID NO:1767 GUUUGAGAUCUGGGACACAtt SEQ ID NO: 1768 GCUGCAAUCGUGGUUUACGtt SEQ IDNO: 1769 UCGUGGUUUACGACAUUACtt SEQ ID NO: 1770 UCAGGAAACCUUUGCCCGAtt SEQID NO: 1771 ACCUUUGCCCGAGCAAAGAtt SEQ ID NO: 1772 AGACAUGGGUGAAGGAACUttSEQ ID NO: 1773 GGAACUACAGCGACAGGCCtt SEQ ID NO: 1774CUACAGCGACAGGCCAGUCtt SEQ ID NO: 1775 CAAAGCUGACCUGGCCAACtt SEQ ID NO:1776 AGCUGACCUGGCCAACAAAtt SEQ ID NO: 1777 CAAACGUAUGGUGGAGUAUtt SEQ IDNO: 1778 ACGUAUGGUGGAGUAUGAAtt SEQ ID NO: 1779 GAGGCCCAGGCAUAUGCAGtt SEQID NO: 1780 CAGCUUAUUGUUCAUGGAGtt SEQ ID NO: 1781 GACAGCUAUGAACGUGAAUttSEQ ID NO: 1782 CGUGAAUGAUCUCUUCCUGtt SEQ ID NO: 1783UGAUCUCUUCCUGGCAAUAtt SEQ ID NO: 1784 UAGCUAAGAAGUUGCCAAAtt SEQ ID NO:1785 GAAGUUGCCAAAGAGUGAAtt SEQ ID NO: 1786 GUUGCCAAAGAGUGAACCCtt SEQ IDNO: 1787 AGAGUGAACCCCAGAAUCUtt SEQ ID NO: 1788 CCCCAGAAUCUGGGAGGUGtt SEQID NO: 1789 UCUGGGAGGUGCAGCAGGCtt SEQ ID NO: 1790 GCCGGGGUGUGGAUCUCCAttSEQ ID NO: 1791 CAGUCCCAGCAGAACAAGAtt SEQ ID NO: 1792CAAGAGCCAGUGUUGUAGCtt SEQ ID NO: 1793 GAGCCAGUGUUGUAGCAACtt SEQ ID NO:1794 CUGAGGGGGUGGCUAGCAGtt SEQ ID NO: 1795 ACAAGUAUGGAGCUAGCACtt SEQ IDNO: 1796 GUAUGGAGCUAGCACAAGAtt SEQ ID NO: 1797 GAGCUAAGAAAUAACCUCCtt SEQID NO: 1798 GAAAUAACCUCCAUCCCUAtt SEQ ID NO: 1799 AUAACCUCCAUCCCUACCCttSEQ ID NO: 1800 CCUCCAUCCCUACCCCUCAtt SEQ ID NO: 1801CCCCUACGGUAACAGCACAtt SEQ ID NO: 1802 CAGCACACUGAGCCCUGGCtt SEQ ID NO:1803 GGGCUGCCUCCUGACAGCUtt SEQ ID NO: 1804 CGCUUCAGCAACAAACACCtt SEQ IDNO: 1805 CAAACACCAGGCAGCUGUUtt SEQ ID NO: 1806 ACACCAGGCAGCUGUUGCCtt SEQID NO: 1807 CUCCCCCCAGGACUUACCUtt SEQ ID NO: 1808 AACAAACUUUCUUCACUUUttSEQ ID NO: 1809 CAAACUUUCUUCACUUUGUtt SEQ ID NO: 1810ACUUUCUUCACUUUGUAUUtt SEQ ID NO: 1811 GACAGCGACUUACGUAUCUtt SEQ ID NO:1812 AACACUUCUGACUCCUGUCtt SEQ ID NO: 1813 CACUUCUGACUCCUGUCCCtt SEQ IDNO: 1814 AGUGGUGAACCCAGGAACUtt SEQ ID NO: 1815 CCCAGGAACUGAGGAAGGAtt SEQID NO: 1816 CUGAGGAAGGAGGUUUCCAtt SEQ ID NO: 1817 GGAGGUUUCCAGUUCAUUUttSEQ ID NO: 1818 GGGCCCUGGGGGAGAAUAAtt SEQ ID NO: 1819UAAAGCUCAGAGCAGGAGGtt SEQ ID NO: 1820 AGCUCAGAGCAGGAGGGAGtt SEQ ID NO:1821 GGAAACAUUUCCUUUUUGUtt SEQ ID NO: 1822 ACAUUUCCUUUUUGUUUUUtt SEQ IDNO: 1823 AACAUUGCGGUAUCCAUGAtt SEQ ID NO: 1824 CAUUGCGGUAUCCAUGAUUtt SEQID NO: 1825 UGGGGAGGCAAGAUCUCAGtt SEQ ID NO: 1826 GAUCUCAGGCACCAGGCAGttSEQ ID NO: 1827 GCUAACUGGGCGGAGGUGGtt SEQ ID NO: 1828CUGGGCGGAGGUGGAGGUGtt SEQ ID NO: 1829 CUGUGGCUCUGUAACUCUUtt SEQ ID NO:1830 CUCUUCAAAGGCCCAGUUUtt SEQ ID NO: 1831 AGGCCCAGUUUCCCCUCACtt SEQ IDNO: 1832 UCGUGGGGGUUGGACCCCAtt SEQ ID NO: 1833 AGAAUUUUCACUGGUUGCCtt SEQID NO: 1834 UUUUCACUGGUUGCCUGCAtt SEQ ID NO: 1835 UUGAUGGUAGUUCAGUUGGttSEQ ID NO: 1836 GUUUUGAUUGAUUUACUUGtt SEQ ID NO: 1837UUCAAUGAAAUCUGAGGUUtt SEQ ID NO: 1838 UGAAAUCUGAGGUUAAUGCtt SEQ ID NO:1839 AUCUGAGGUUAAUGCGAGGtt SEQ ID NO: 1840 UGCGAGGUUCGAGGAGAGGtt SEQ IDNO: 1841 AACUACCAGUGGCAGCUACtt SEQ ID NO: 1842 CUACCAGUGGCAGCUACUCtt SEQID NO: 1843 GUCCUAUCUCCACUGUUAGtt SEQ ID NO: 1844 CUCUAAUUAUUAACCUAUAttSEQ ID NO: 1845 UUAUUAACCUAUAUUCUUGtt SEQ ID NO: 1846CCUAUAUUCUUGCCAAGCUtt SEQ ID NO: 1847 GCUAACUAUUGACUAUAGGtt SEQ ID NO:1848 CUAUUGACUAUAGGUUUGCtt SEQ ID NO: 1849 UUAAUUGAGCAAUUGAGGAtt SEQ IDNO: 1850 UUGAGCAAUUGAGGAGUGUtt SEQ ID NO: 1851 UUGAGGAGUGUCUCAGGAUtt SEQID NO: 1852 GGUAGGGGAGUAAAAAGGAtt SEQ ID NO: 1853 AAAGGAGGUCAGGCAAAAGttSEQ ID NO: 1854 AGGAGGUCAGGCAAAAGGGtt SEQ ID NO: 1855AAGGGAGGAGUUUUCUGUCtt SEQ ID NO: 1856 GGGAGGAGUUUUCUGUCCUtt SEQ ID NO:1857 UUUGAUAUCCAUUACCAUGtt SEQ ID NO: 1858 AUAGGUAUGAUCUUUAUUCtt SEQ IDNO: 1859 UAUCUUGAAUUUAGUCCCUtt SEQ ID NO: 1860 UUUAGUCCCUCCAUCCUUAtt SEQID NO: 1861 UCCCCCCAUCCCUCCCCAUtt SEQ ID NO: 1862 CCAGUGGUUUAAUCCAUGUttSEQ ID NO: 1863 UCCAUGUACCAAUAGGGGCtt SEQ ID NO: 1864UAGGGGCUAGUACCACAGAtt SEQ ID NO: 1865 UGACCGGCACUGAAGGUACtt SEQ ID NO:1866 GGUACCUUACAACUGGCUCtt SEQ ID NO: 1867 CUGGCUCAUAUUAUCAGAGtt SEQ IDNO: 1868 AUCUCUAGUCUCUCUUCAUtt SEQ ID NO: 1869 GAUGUCUCUGAGAAGCCAUtt SEQID NO: 1870 GCCAUCAAGGCAAAAGAGAtt SEQ ID NO: 1871 GGCAAAAGAGAACUUUAAGttSEQ ID NO: 1872 AAGAGAACUUUAAGUUCCUtt SEQ ID NO: 1873GAGAACUUUAAGUUCCUUGtt SEQ ID NO: 1874 CUUUAAGUUCCUUGUUCCAtt SEQ ID NO:1875 GUUCCUUGUUCCAGCCCGGtt SEQ ID NO: 1876 AGAAAGAAAGGAAAGGUCAtt SEQ IDNO: 1877 AGAAAGGAAAGGUCACAGUtt SEQ ID NO: 1878 AGGAAAGGUCACAGUGACCtt SEQID NO: 1879 AGGUCACAGUGACCUAGGAtt SEQ ID NO: 1880 CCUUCCUGCCCUUUUGGCUttSEQ ID NO: 1881 CAGCUGAGAAAUCUAUGAAtt SEQ ID NO: 1882AUCUAUGAAGCUGAGAUUCtt SEQ ID NO: 1883 GCUGAGAUUCUGAAGGACCtt SEQ ID NO:1884 GGACCCAGCUUAGGUUCUUtt SEQ ID NO: 1885 UUCCCUUCCUUUUCCAGGGtt SEQ IDNO: 1886 ACACACACAUUUCCCCCUUtt SEQ ID NO: 1887 GCCACUGGCCCCCCAUAGCtt SEQID NO: 1888 GUGGAAGAACUAGGAUGGCtt SEQ ID NO: 1889 GAACUAGGAUGGCUUUCCAttSEQ ID NO: 1890 CUAGGAUGGCUUUCCAAAGtt SEQ ID NO: 1891AGUCUUCUAGAAAUGAAGUtt SEQ ID NO: 1892 AUGAAGUUCUUUCUCUGUGtt SEQ ID NO:1893 GUUCUUUCUCUGUGCAGCUtt SEQ ID NO: 1894 GAUGUUUCAUUAUCUUGGGtt SEQ IDNO: 1895 ACCACUUCCCCAGGCUUCUtt SEQ ID NO: 1896 CAGGAUUUGGCCUUAGCUUtt SEQID NO: 1897 GGGGGGGUGUUGUGGUUUUtt SEQ ID NO: 1898 AGCAUUUGCCUUUCUUCCUttSEQ ID NO: 1899 CAUAACAAUCGUGGUAACAtt SEQ ID NO: 1900CAAUCGUGGUAACAGAAUGtt SEQ ID NO: 1901 UCGUGGUAACAGAAUGCGAtt SEQ ID NO:1902 CAGAAUGCGACUGCUGAUUtt SEQ ID NO: 1903 UGCGACUGCUGAUUUACCGtt SEQ IDNO: 1904 UGUAAGUAAAAAAAGGAAAtt SEQ ID NO: 1905 GUAAAAAAAGGAAAAAAAGtt SEQID NO: 1906 AAAAAGGAAAAAAAGAAAAtt SEQ ID NO: 1907 AAAGGAAAAAAAGAAAAAAttSEQ ID NO: 1908 AGGAAAAAAAGAAAAAAAAtt SEQ ID NO: 1909AAAAAGAAAAAAAAAAAAAtt SEQ ID NO: 1910 AAAGAAAAAAAAAAAAAAAtt SEQ ID NO:1911 AGAAAAAAAAAAAAAAAAAtt SEQ ID NO: 1912 AAAAAAAAAAAAAAAAAAAtt

TABLE 9 Candidate siRNAs for RPS26, SEQ ID NOs: 1913-2002 are based onNM_001029. SEQ ID NO: 1913 UGGCGGAAGAAAAUCGAGGtt SEQ ID NO: 1914AAAGUGCACAUGGGACUAUtt SEQ ID NO: 1915 AUGCGUUCCUAGUGUUUAUtt SEQ ID NO:1916 GGAAAUGCGUUCCUAGUGUtt SEQ ID NO: 1917 AAUCUAGGGUGGAAAUGCGtt SEQ IDNO: 1918 AUUCCUUUACAUUCAGCAUtt SEQ ID NO: 1919 ACUCAAAUAUUCCUUUACAtt SEQID NO: 1920 ACUUUACUCAAAUAUUCCUtt SEQ ID NO: 1921 AACUCACUUUACUCAAAUAttSEQ ID NO: 1922 UCAAGAACGGCAACUCACUtt SEQ ID NO: 1923GAAUCCUUAGGAGACGGGCtt SEQ ID NO: 1924 GCGGACACCGGGAGAAUCCtt SEQ ID NO:1925 CCUUCUUUUCUUUGUCAUCtt SEQ ID NO: 1926 CCAUUGUUCCUUCUUUUCUtt SEQ IDNO: 1927 ACGACCAUUGUUCCUUCUUtt SEQ ID NO: 1928 GCACGACCAUUGUUCCUUCtt SEQID NO: 1929 UUGGCACGACCAUUGUUCCtt SEQ ID NO: 1930 CUUUUUGGCACGACCAUUGttSEQ ID NO: 1931 GCCCUUUUUGGCACGACCAtt SEQ ID NO: 1932CACGUGGCCGCGGCCCUUUtt SEQ ID NO: 1933 UGCACGUGGCCGCGGCCCUtt SEQ ID NO:1934 GGGCACGCAUCGGGCACAGtt SEQ ID NO: 1935 UUUCUUAAUGGCCUUGUCCtt SEQ IDNO: 1936 GACGAAUUUCUUAAUGGCCtt SEQ ID NO: 1937 GUUUCGAAUGACGAAUUUCtt SEQID NO: 1938 UAUGUUUCGAAUGACGAAUtt SEQ ID NO: 1939 GCUGCGGCCUCCACUAUGUttSEQ ID NO: 1940 AGGCAUCGAAGACGCUCGCtt SEQ ID NO: 1941AUGUAGCUUCACAUACAGCtt SEQ ID NO: 1942 ACUCACACAGUAAUGUAGCtt SEQ ID NO:1943 CUGACUACUUUGCUGUGAAtt SEQ ID NO: 1944 AGAUCGAUUCCUGACUACUtt SEQ IDNO: 1945 GCGGGCUUCACGAGAUCGAtt SEQ ID NO: 1946 GUGUUCGGUCCUUGCGGGCtt SEQID NO: 1947 GGGUGGGGGUGUUCGGUCCtt SEQ ID NO: 1948 CUAAAUCGGGGUGGGGGUGttSEQ ID NO: 1949 UCAGCUCCUUACAUGGGCUtt SEQ ID NO: 1950UCUUUAAGAACUCAGCUCCtt SEQ ID NO: 1951 AAUAGCCUGUCUUCAGUCUtt SEQ ID NO:1952 CUCCAGAGAAUAGCCUGUCtt SEQ ID NO: 1953 UACAAUUUCCAUUUUAUUUtt SEQ IDNO: 1954 AGUACAAUUUCCAUUUUAUtt SEQ ID NO: 1955 UUUAAGUACAAUUUCCAUUtt SEQID NO: 1956 UUUUUAAGUACAAUUUCCAtt SEQ ID NO: 1957 UUUUUUUUUUAAGUACAAUttSEQ ID NO: 1958 CCUCGAUUUUCUUCCGCCAtt SEQ ID NO: 1959AUAGUCCCAUGUGCACUUUtt SEQ ID NO: 1960 AUAAACACUAGGAACGCAUtt SEQ ID NO:1961 ACACUAGGAACGCAUUUCCtt SEQ ID NO: 1962 CGCAUUUCCACCCUAGAUUtt SEQ IDNO: 1963 AUGCUGAAUGUAAAGGAAUtt SEQ ID NO: 1964 UGUAAAGGAAUAUUUGAGUtt SEQID NO: 1965 AGGAAUAUUUGAGUAAAGUtt SEQ ID NO: 1966 UAUUUGAGUAAAGUGAGUUttSEQ ID NO: 1967 AGUGAGUUGCCGUUCUUGAtt SEQ ID NO: 1968GCCCGUCUCCUAAGGAUUCtt SEQ ID NO: 1969 GGAUUCUCCCGGUGUCCGCtt SEQ ID NO:1970 GAUGACAAAGAAAAGAAGGtt SEQ ID NO: 1971 AGAAAAGAAGGAACAAUGGtt SEQ IDNO: 1972 AAGAAGGAACAAUGGUCGUtt SEQ ID NO: 1973 GAAGGAACAAUGGUCGUGCtt SEQID NO: 1974 GGAACAAUGGUCGUGCCAAtt SEQ ID NO: 1975 CAAUGGUCGUGCCAAAAAGttSEQ ID NO: 1976 UGGUCGUGCCAAAAAGGGCtt SEQ ID NO: 1977AAAGGGCCGCGGCCACGUGtt SEQ ID NO: 1978 AGGGCCGCGGCCACGUGCAtt SEQ ID NO:1979 CUGUGCCCGAUGCGUGCCCtt SEQ ID NO: 1980 GGACAAGGCCAUUAAGAAAtt SEQ IDNO: 1981 GGCCAUUAAGAAAUUCGUCtt SEQ ID NO: 1982 GAAAUUCGUCAUUCGAAACtt SEQID NO: 1983 AUUCGUCAUUCGAAACAUAtt SEQ ID NO: 1984 ACAUAGUGGAGGCCGCAGCttSEQ ID NO: 1985 GCGAGCGUCUUCGAUGCCUtt SEQ ID NO: 1986GCUGUAUGUGAAGCUACAUtt SEQ ID NO: 1987 GCUACAUUACUGUGUGAGUtt SEQ ID NO:1988 UUCACAGCAAAGUAGUCAGtt SEQ ID NO: 1989 AGUAGUCAGGAAUCGAUCUtt SEQ IDNO: 1990 UCGAUCUCGUGAAGCCCGCtt SEQ ID NO: 1991 GCCCGCAAGGACCGAACACtt SEQID NO: 1992 GGACCGAACACCCCCACCCtt SEQ ID NO: 1993 CACCCCCACCCCGAUUUAGttSEQ ID NO: 1994 AGCCCAUGUAAGGAGCUGAtt SEQ ID NO: 1995GGAGCUGAGUUCUUAAAGAtt SEQ ID NO: 1996 AGACUGAAGACAGGCUAUUtt SEQ ID NO:1997 GACAGGCUAUUCUCUGGAGtt SEQ ID NO: 1998 AAAUAAAAUGGAAAUUGUAtt SEQ IDNO: 1999 AUAAAAUGGAAAUUGUACUtt SEQ ID NO: 2000 AAUGGAAAUUGUACUUAAAtt SEQID NO: 2001 UGGAAAUUGUACUUAAAAAtt SEQ ID NO: 2002 AUUGUACUUAAAAAAAAAAtt

TABLE 10 Candidate siRNAs for SUOX, SEQ ID NOs: 2003-2204 are based onNM_000456, SEQ ID NOs: 2205-2394 are based on NM_001032386, and SEQ IDNOs: 2395-2576 are based on NM_001032387. SEQ ID NO: 2003AGGGGCGGGGCCAGCGCCGtt SEQ ID NO: 2004 ACCAGCCCAGCUCUGCGAGtt SEQ ID NO:2005 UGUCUUCAGCACUGCAAUUtt SEQ ID NO: 2006 AGUGUCUUCAGCACUGCAAtt SEQ IDNO: 2007 CUUUUGCGGGUCCAGUGUCtt SEQ ID NO: 2008 GUUUGGGAGGGACAGCCUUtt SEQID NO: 2009 AGGUUUGGGAGGGACAGCCtt SEQ ID NO: 2010 UGAGCCCAGAAUCCCAGGUttSEQ ID NO: 2011 CUCAAUGCCAGCAGCCUGUtt SEQ ID NO: 2012GACUGCUAGAGGCCAGGAGtt SEQ ID NO: 2013 UUCCGGACACACUAGCACUtt SEQ ID NO:2014 GAGACCAAGAACCCACCAAtt SEQ ID NO: 2015 AGGGUCCGCGGCUUCAUUCtt SEQ IDNO: 2016 GCGAGGGUCCGCGGCUUCAtt SEQ ID NO: 2017 GACUGCGAGGGUCCGCGGCtt SEQID NO: 2018 GCUCUGUGCAGCAGCAGCAtt SEQ ID NO: 2019 ACUUGAGUCUGCAGGCCUGttSEQ ID NO: 2020 GAUCCUUGAGGGGAUUGACtt SEQ ID NO: 2021AUGCAGAUCCUUGAGGGGAtt SEQ ID NO: 2022 CAGGCCUGAAUGCAGAUCCtt SEQ ID NO:2023 UGGGGCUGAAAUGAAUCAUtt SEQ ID NO: 2024 CCAUCCCUGGGUGCUGGAGtt SEQ IDNO: 2025 UCCUUAGUGUAUAUGUGUGtt SEQ ID NO: 2026 GUGGGAACUCACUUCCUCCtt SEQID NO: 2027 GGCUGGUGUGGGAACUCACtt SEQ ID NO: 2028 CUGGAUGUAGGUCCACAAAttSEQ ID NO: 2029 CCAGCUGCUAGCAUCAGCUtt SEQ ID NO: 2030CUCACGCACAUGGGACUGGtt SEQ ID NO: 2031 AGGAUUCAGCUCCCCAAUCtt SEQ ID NO:2032 GGCUACCUUGUCUUCAGGAtt SEQ ID NO: 2033 CGGUGGGGGCUACCUUGUCtt SEQ IDNO: 2034 CUCCACGGUGGGGGCUACCtt SEQ ID NO: 2035 GGGCCGCUGGCUGUUGACCtt SEQID NO: 2036 AUUAAAGGGCCGCUGGCUGtt SEQ ID NO: 2037 CUCAGGGGGAGGCUCUGCAttSEQ ID NO: 2038 GGUUGGGUGUGAUGUAGUUtt SEQ ID NO: 2039AGGGUUGGGUGUGAUGUAGtt SEQ ID NO: 2040 CCGGGUGAAGAAGAUAGGGtt SEQ ID NO:2041 GUUAGGUACAGGCAGAUGGtt SEQ ID NO: 2042 AUAGGUGUCUGGAUCCAGGtt SEQ IDNO: 2043 GAUCUCGUACCUGGGAAAGtt SEQ ID NO: 2044 AGUCAUCUCAGAGCGUCGGtt SEQID NO: 2045 CUCCAGACCUUUUACUUCUtt SEQ ID NO: 2046 UCCACUCCAGACCUUUUACttSEQ ID NO: 2047 GUUCUCCACUCCAGACCUUtt SEQ ID NO: 2048CUGUUCUCCACUCCAGACCtt SEQ ID NO: 2049 GCAGUGCUGAUGGCUCCUGtt SEQ ID NO:2050 GGGCCUCAGUUUCACAGAGtt SEQ ID NO: 2051 AGCAGACGUGGGCCUCAGUtt SEQ IDNO: 2052 AUGCCAGCAGGACCUCAGCtt SEQ ID NO: 2053 ACGUGGCAGAGGCUGCCCAtt SEQID NO: 2054 ACUCACUCUGCCCAGCCAUtt SEQ ID NO: 2055 GUUGCCAGUGGCUGUAACUttSEQ ID NO: 2056 AGCCUUUGUAAUCCCGCCGtt SEQ ID NO: 2057CACAGAUGGAGAGAAGCCUtt SEQ ID NO: 2058 UGGCCGACUGGACAGGAAGtt SEQ ID NO:2059 UGAUGGUCACCUCCCCUGAtt SEQ ID NO: 2060 ACCACUCCAUGCAUAGCCCtt SEQ IDNO: 2061 AGCUUAGCCACCUGCCAGGtt SEQ ID NO: 2062 CUGUUCCUCUCCAUCCAGCtt SEQID NO: 2063 AGGCCUUCCUGGGGCGCUGtt SEQ ID NO: 2064 CAGACGCCAUGCCCAGGCCttSEQ ID NO: 2065 UCCAGCUGGCACAGGGGCUtt SEQ ID NO: 2066AAACAAUGUUCAGUUCCUUtt SEQ ID NO: 2067 ACAAACAAUGUUCAGUUCCtt SEQ ID NO:2068 CCUUACAAACAAUGUUCAGtt SEQ ID NO: 2069 CACAGCCUUACAAACAAUGtt SEQ IDNO: 2070 GUAACCAUCAUCCACAGCCtt SEQ ID NO: 2071 CACGGUGUCUGGCUGCACAtt SEQID NO: 2072 ACACCUCGCAGGUUCCAGAtt SEQ ID NO: 2073 GCUGAGAACACCUCGCAGGttSEQ ID NO: 2074 AUGGACACGAUGCCAGGCAtt SEQ ID NO: 2075AGGGGUGGAGGUGGCUCCUtt SEQ ID NO: 2076 UGAAAGGUGGGAAAGAUUUtt SEQ ID NO:2077 GUUGAAAGGUGGGAAAGAUtt SEQ ID NO: 2078 AGAGUUGUGAUCCAAGAAGtt SEQ IDNO: 2079 UGGCUUAGGAAGGCCAGAGtt SEQ ID NO: 2080 AUGUGUACUUGGGUAUGGCtt SEQID NO: 2081 AAAUGUGCUAUAUGUGUACtt SEQ ID NO: 2082 GUCCAAAGAGGGAAGGUCCttSEQ ID NO: 2083 UCACACUUCCUGGCACAGGtt SEQ ID NO: 2084UUGCUGUAACAGCUCACACtt SEQ ID NO: 2085 UUUUUUCACUUCUAGCCCCtt SEQ ID NO:2086 CCAGAAUUACUUUUUUCACtt SEQ ID NO: 2087 UGUCUCCAGAAUUACUUUUtt SEQ IDNO: 2088 CUUGUCUCCAGAAUUACUUtt SEQ ID NO: 2089 UGCUUGUCUCCAGAAUUACtt SEQID NO: 2090 AUAGUGCUUGUCUCCAGAAtt SEQ ID NO: 2091 UAGGAAGAGAAAAUAGUGCttSEQ ID NO: 2092 GCCUUGAUGGCAGUAGGCAtt SEQ ID NO: 2093AGAAAAGCAAAACAAGGCCtt SEQ ID NO: 2094 UUACACAUGCCACACACAUtt SEQ ID NO:2095 GAUAGUAUAUACACUUUUCtt SEQ ID NO: 2096 UAAGAUAGUAUAUACACUUtt SEQ IDNO: 2097 UAUAAGAUAGUAUAUACACtt SEQ ID NO: 2098 AGGGAGACGGUUGUGCCCCtt SEQID NO: 2099 GAACUAUAAAGGGAGACGGtt SEQ ID NO: 2100 AUCUUAAACAGACUAUUUAttSEQ ID NO: 2101 AUGAUCUUAAACAGACUAUtt SEQ ID NO: 2102UUUUUUUUUUUUUAUGAUCtt SEQ ID NO: 2103 UUUUUUUUUUUUUUUUUUUtt SEQ ID NO:2104 CGGCGCUGGCCCCGCCCCUtt SEQ ID NO: 2105 CUCGCAGAGCUGGGCUGGUtt SEQ IDNO: 2106 AAUUGCAGUGCUGAAGACAtt SEQ ID NO: 2107 UUGCAGUGCUGAAGACACUtt SEQID NO: 2108 GACACUGGACCCGCAAAAGtt SEQ ID NO: 2109 AAGGCUGUCCCUCCCAAACttSEQ ID NO: 2110 GGCUGUCCCUCCCAAACCUtt SEQ ID NO: 2111ACCUGGGAUUCUGGGCUCAtt SEQ ID NO: 2112 ACAGGCUGCUGGCAUUGAGtt SEQ ID NO:2113 CUCCUGGCCUCUAGCAGUCtt SEQ ID NO: 2114 AGUGCUAGUGUGUCCGGAAtt SEQ IDNO: 2115 UUGGUGGGUUCUUGGUCUCtt SEQ ID NO: 2116 GAAUGAAGCCGCGGACCCUtt SEQID NO: 2117 UGAAGCCGCGGACCCUCGCtt SEQ ID NO: 2118 GCCGCGGACCCUCGCAGUCttSEQ ID NO: 2119 UGCUGCUGCUGCACAGAGCtt SEQ ID NO: 2120CAGGCCUGCAGACUCAAGUtt SEQ ID NO: 2121 GUCAAUCCCCUCAAGGAUCtt SEQ ID NO:2122 UCCCCUCAAGGAUCUGCAUtt SEQ ID NO: 2123 GGAUCUGCAUUCAGGCCUGtt SEQ IDNO: 2124 AUGAUUCAUUUCAGCCCCAtt SEQ ID NO: 2125 CUCCAGCACCCAGGGAUGGtt SEQID NO: 2126 CACACAUAUACACUAAGGAtt SEQ ID NO: 2127 GGAGGAAGUGAGUUCCCACttSEQ ID NO: 2128 GUGAGUUCCCACACCAGCCtt SEQ ID NO: 2129UUUGUGGACCUACAUCCAGtt SEQ ID NO: 2130 AGCUGAUGCUAGCAGCUGGtt SEQ ID NO:2131 CCAGUCCCAUGUGCGUGAGtt SEQ ID NO: 2132 GAUUGGGGAGCUGAAUCCUtt SEQ IDNO: 2133 UCCUGAAGACAAGGUAGCCtt SEQ ID NO: 2134 GACAAGGUAGCCCCCACCGtt SEQID NO: 2135 GGUAGCCCCCACCGUGGAGtt SEQ ID NO: 2136 GGUCAACAGCCAGCGGCCCttSEQ ID NO: 2137 CAGCCAGCGGCCCUUUAAUtt SEQ ID NO: 2138UGCAGAGCCUCCCCCUGAGtt SEQ ID NO: 2139 AACUACAUCACACCCAACCtt SEQ ID NO:2140 CUACAUCACACCCAACCCUtt SEQ ID NO: 2141 CCCUAUCUUCUUCACCCGGtt SEQ IDNO: 2142 CCAUCUGCCUGUACCUAACtt SEQ ID NO: 2143 CCUGGAUCCAGACACCUAUtt SEQID NO: 2144 CUUUCCCAGGUACGAGAUCtt SEQ ID NO: 2145 CCGACGCUCUGAGAUGACUttSEQ ID NO: 2146 AGAAGUAAAAGGUCUGGAGtt SEQ ID NO: 2147GUAAAAGGUCUGGAGUGGAtt SEQ ID NO: 2148 AAGGUCUGGAGUGGAGAACtt SEQ ID NO:2149 GGUCUGGAGUGGAGAACAGtt SEQ ID NO: 2150 CAGGAGCCAUCAGCACUGCtt SEQ IDNO: 2151 CUCUGUGAAACUGAGGCCCtt SEQ ID NO: 2152 ACUGAGGCCCACGUCUGCUtt SEQID NO: 2153 GCUGAGGUCCUGCUGGCAUtt SEQ ID NO: 2154 UGGGCAGCCUCUGCCACGUttSEQ ID NO: 2155 AUGGCUGGGCAGAGUGAGUtt SEQ ID NO: 2156AGUUACAGCCACUGGCAACtt SEQ ID NO: 2157 CGGCGGGAUUACAAAGGCUtt SEQ ID NO:2158 AGGCUUCUCUCCAUCUGUGtt SEQ ID NO: 2159 CUUCCUGUCCAGUCGGCCAtt SEQ IDNO: 2160 UCAGGGGAGGUGACCAUCAtt SEQ ID NO: 2161 GGGCUAUGCAUGGAGUGGUtt SEQID NO: 2162 CCUGGCAGGUGGCUAAGCUtt SEQ ID NO: 2163 GCUGGAUGGAGAGGAACAGttSEQ ID NO: 2164 CAGCGCCCCAGGAAGGCCUtt SEQ ID NO: 2165GGCCUGGGCAUGGCGUCUGtt SEQ ID NO: 2166 AGCCCCUGUGCCAGCUGGAtt SEQ ID NO:2167 AAGGAACUGAACAUUGUUUtt SEQ ID NO: 2168 GGAACUGAACAUUGUUUGUtt SEQ IDNO: 2169 CUGAACAUUGUUUGUAAGGtt SEQ ID NO: 2170 CAUUGUUUGUAAGGCUGUGtt SEQID NO: 2171 GGCUGUGGAUGAUGGUUACtt SEQ ID NO: 2172 UGUGCAGCCAGACACCGUGttSEQ ID NO: 2173 UCUGGAACCUGCGAGGUGUtt SEQ ID NO: 2174CCUGCGAGGUGUUCUCAGCtt SEQ ID NO: 2175 UGCCUGGCAUCGUGUCCAUtt SEQ ID NO:2176 AGGAGCCACCUCCACCCCUtt SEQ ID NO: 2177 AAAUCUUUCCCACCUUUCAtt SEQ IDNO: 2178 AUCUUUCCCACCUUUCAACtt SEQ ID NO: 2179 CUUCUUGGAUCACAACUCUtt SEQID NO: 2180 CUCUGGCCUUCCUAAGCCAtt SEQ ID NO: 2181 GCCAUACCCAAGUACACAUttSEQ ID NO: 2182 GUACACAUAUAGCACAUUUtt SEQ ID NO: 2183GGACCUUCCCUCUUUGGACtt SEQ ID NO: 2184 CCUGUGCCAGGAAGUGUGAtt SEQ ID NO:2185 GUGUGAGCUGUUACAGCAAtt SEQ ID NO: 2186 GGGGCUAGAAGUGAAAAAAtt SEQ IDNO: 2187 GUGAAAAAAGUAAUUCUGGtt SEQ ID NO: 2188 AAAAGUAAUUCUGGAGACAtt SEQID NO: 2189 AAGUAAUUCUGGAGACAAGtt SEQ ID NO: 2190 GUAAUUCUGGAGACAAGCAttSEQ ID NO: 2191 UUCUGGAGACAAGCACUAUtt SEQ ID NO: 2192GCACUAUUUUCUCUUCCUAtt SEQ ID NO: 2193 UGCCUACUGCCAUCAAGGCtt SEQ ID NO:2194 GGCCUUGUUUUGCUUUUCUtt SEQ ID NO: 2195 AUGUGUGUGGCAUGUGUAAtt SEQ IDNO: 2196 GAAAAGUGUAUAUACUAUCtt SEQ ID NO: 2197 AAGUGUAUAUACUAUCUUAtt SEQID NO: 2198 GUGUAUAUACUAUCUUAUAtt SEQ ID NO: 2199 GGGGCACAACCGUCUCCCUttSEQ ID NO: 2200 CCGUCUCCCUUUAUAGUUCtt SEQ ID NO: 2201UAAAUAGUCUGUUUAAGAUtt SEQ ID NO: 2202 AUAGUCUGUUUAAGAUCAUtt SEQ ID NO:2203 GAUCAUAAAAAAAAAAAAAtt SEQ ID NO: 2204 AAAAAAAAAAAAAAAAAAAtt SEQ IDNO: 2205 AGGGGCGGGGCCAGCGCCGtt SEQ ID NO: 2206 ACCAGCCCAGCUCUGCGAGtt SEQID NO: 2207 UGUCUUCAGCACUGCAAUUtt SEQ ID NO: 2208 AGUGUCUUCAGCACUGCAAttSEQ ID NO: 2209 CUUUUGCGGGUCCAGUGUCtt SEQ ID NO: 2210GUUUGGGAGGGACAGCCUUtt SEQ ID NO: 2211 AGGUUUGGGAGGGACAGCCtt SEQ ID NO:2212 UGAGCCCAGAAUCCCAGGUtt SEQ ID NO: 2213 CUCAAUGCCAGCAGCCUGUtt SEQ IDNO: 2214 GCUCUGUGCAGCAGCAGCAtt SEQ ID NO: 2215 ACUUGAGUCUGCAGGCCUGtt SEQID NO: 2216 GAUCCUUGAGGGGAUUGACtt SEQ ID NO: 2217 AUGCAGAUCCUUGAGGGGAttSEQ ID NO: 2218 CAGGCCUGAAUGCAGAUCCtt SEQ ID NO: 2219UGGGGCUGAAAUGAAUCAUtt SEQ ID NO: 2220 CCAUCCCUGGGUGCUGGAGtt SEQ ID NO:2221 UCCUUAGUGUAUAUGUGUGtt SEQ ID NO: 2222 GUGGGAACUCACUUCCUCCtt SEQ IDNO: 2223 GGCUGGUGUGGGAACUCACtt SEQ ID NO: 2224 CUGGAUGUAGGUCCACAAAtt SEQID NO: 2225 CCAGCUGCUAGCAUCAGCUtt SEQ ID NO: 2226 CUCACGCACAUGGGACUGGttSEQ ID NO: 2227 AGGAUUCAGCUCCCCAAUCtt SEQ ID NO: 2228GGCUACCUUGUCUUCAGGAtt SEQ ID NO: 2229 CGGUGGGGGCUACCUUGUCtt SEQ ID NO:2230 CUCCACGGUGGGGGCUACCtt SEQ ID NO: 2231 GGGCCGCUGGCUGUUGACCtt SEQ IDNO: 2232 AUUAAAGGGCCGCUGGCUGtt SEQ ID NO: 2233 CUCAGGGGGAGGCUCUGCAtt SEQID NO: 2234 GGUUGGGUGUGAUGUAGUUtt SEQ ID NO: 2235 AGGGUUGGGUGUGAUGUAGttSEQ ID NO: 2236 CCGGGUGAAGAAGAUAGGGtt SEQ ID NO: 2237GUUAGGUACAGGCAGAUGGtt SEQ ID NO: 2238 AUAGGUGUCUGGAUCCAGGtt SEQ ID NO:2239 GAUCUCGUACCUGGGAAAGtt SEQ ID NO: 2240 AGUCAUCUCAGAGCGUCGGtt SEQ IDNO: 2241 CUCCAGACCUUUUACUUCUtt SEQ ID NO: 2242 UCCACUCCAGACCUUUUACtt SEQID NO: 2243 GUUCUCCACUCCAGACCUUtt SEQ ID NO: 2244 CUGUUCUCCACUCCAGACCttSEQ ID NO: 2245 GCAGUGCUGAUGGCUCCUGtt SEQ ID NO: 2246GGGCCUCAGUUUCACAGAGtt SEQ ID NO: 2247 AGCAGACGUGGGCCUCAGUtt SEQ ID NO:2248 AUGCCAGCAGGACCUCAGCtt SEQ ID NO: 2249 ACGUGGCAGAGGCUGCCCAtt SEQ IDNO: 2250 ACUCACUCUGCCCAGCCAUtt SEQ ID NO: 2251 GUUGCCAGUGGCUGUAACUtt SEQID NO: 2252 AGCCUUUGUAAUCCCGCCGtt SEQ ID NO: 2253 CACAGAUGGAGAGAAGCCUttSEQ ID NO: 2254 UGGCCGACUGGACAGGAAGtt SEQ ID NO: 2255UGAUGGUCACCUCCCCUGAtt SEQ ID NO: 2256 ACCACUCCAUGCAUAGCCCtt SEQ ID NO:2257 AGCUUAGCCACCUGCCAGGtt SEQ ID NO: 2258 CUGUUCCUCUCCAUCCAGCtt SEQ IDNO: 2259 AGGCCUUCCUGGGGCGCUGtt SEQ ID NO: 2260 CAGACGCCAUGCCCAGGCCtt SEQID NO: 2261 UCCAGCUGGCACAGGGGCUtt SEQ ID NO: 2262 AAACAAUGUUCAGUUCCUUttSEQ ID NO: 2263 ACAAACAAUGUUCAGUUCCtt SEQ ID NO: 2264CCUUACAAACAAUGUUCAGtt SEQ ID NO: 2265 CACAGCCUUACAAACAAUGtt SEQ ID NO:2266 GUAACCAUCAUCCACAGCCtt SEQ ID NO: 2267 CACGGUGUCUGGCUGCACAtt SEQ IDNO: 2268 ACACCUCGCAGGUUCCAGAtt SEQ ID NO: 2269 GCUGAGAACACCUCGCAGGtt SEQID NO: 2270 AUGGACACGAUGCCAGGCAtt SEQ ID NO: 2271 AGGGGUGGAGGUGGCUCCUttSEQ ID NO: 2272 UGAAAGGUGGGAAAGAUUUtt SEQ ID NO: 2273GUUGAAAGGUGGGAAAGAUtt SEQ ID NO: 2274 AGAGUUGUGAUCCAAGAAGtt SEQ ID NO:2275 UGGCUUAGGAAGGCCAGAGtt SEQ ID NO: 2276 AUGUGUACUUGGGUAUGGCtt SEQ IDNO: 2277 AAAUGUGCUAUAUGUGUACtt SEQ ID NO: 2278 GUCCAAAGAGGGAAGGUCCtt SEQID NO: 2279 UCACACUUCCUGGCACAGGtt SEQ ID NO: 2280 UUGCUGUAACAGCUCACACttSEQ ID NO: 2281 UUUUUUCACUUCUAGCCCCtt SEQ ID NO: 2282CCAGAAUUACUUUUUUCACtt SEQ ID NO: 2283 UGUCUCCAGAAUUACUUUUtt SEQ ID NO:2284 CUUGUCUCCAGAAUUACUUtt SEQ ID NO: 2285 UGCUUGUCUCCAGAAUUACtt SEQ IDNO: 2286 AUAGUGCUUGUCUCCAGAAtt SEQ ID NO: 2287 UAGGAAGAGAAAAUAGUGCtt SEQID NO: 2288 GCCUUGAUGGCAGUAGGCAtt SEQ ID NO: 2289 AGAAAAGCAAAACAAGGCCttSEQ ID NO: 2290 UUACACAUGCCACACACAUtt SEQ ID NO: 2291GAUAGUAUAUACACUUUUCtt SEQ ID NO: 2292 UAAGAUAGUAUAUACACUUtt SEQ ID NO:2293 UAUAAGAUAGUAUAUACACtt SEQ ID NO: 2294 AGGGAGACGGUUGUGCCCCtt SEQ IDNO: 2295 GAACUAUAAAGGGAGACGGtt SEQ ID NO: 2296 AUCUUAAACAGACUAUUUAtt SEQID NO: 2297 AUGAUCUUAAACAGACUAUtt SEQ ID NO: 2298 UUUUUUUUUUUUUAUGAUCttSEQ ID NO: 2299 UUUUUUUUUUUUUUUUUUUtt SEQ ID NO: 2300CGGCGCUGGCCCCGCCCCUtt SEQ ID NO: 2301 CUCGCAGAGCUGGGCUGGUtt SEQ ID NO:2302 AAUUGCAGUGCUGAAGACAtt SEQ ID NO: 2303 UUGCAGUGCUGAAGACACUtt SEQ IDNO: 2304 GACACUGGACCCGCAAAAGtt SEQ ID NO: 2305 AAGGCUGUCCCUCCCAAACtt SEQID NO: 2306 GGCUGUCCCUCCCAAACCUtt SEQ ID NO: 2307 ACCUGGGAUUCUGGGCUCAttSEQ ID NO: 2308 ACAGGCUGCUGGCAUUGAGtt SEQ ID NO: 2309UGCUGCUGCUGCACAGAGCtt SEQ ID NO: 2310 CAGGCCUGCAGACUCAAGUtt SEQ ID NO:2311 GUCAAUCCCCUCAAGGAUCtt SEQ ID NO: 2312 UCCCCUCAAGGAUCUGCAUtt SEQ IDNO: 2313 GGAUCUGCAUUCAGGCCUGtt SEQ ID NO: 2314 AUGAUUCAUUUCAGCCCCAtt SEQID NO: 2315 CUCCAGCACCCAGGGAUGGtt SEQ ID NO: 2316 CACACAUAUACACUAAGGAttSEQ ID NO: 2317 GGAGGAAGUGAGUUCCCACtt SEQ ID NO: 2318GUGAGUUCCCACACCAGCCtt SEQ ID NO: 2319 UUUGUGGACCUACAUCCAGtt SEQ ID NO:2320 AGCUGAUGCUAGCAGCUGGtt SEQ ID NO: 2321 CCAGUCCCAUGUGCGUGAGtt SEQ IDNO: 2322 GAUUGGGGAGCUGAAUCCUtt SEQ ID NO: 2323 UCCUGAAGACAAGGUAGCCtt SEQID NO: 2324 GACAAGGUAGCCCCCACCGtt SEQ ID NO: 2325 GGUAGCCCCCACCGUGGAGttSEQ ID NO: 2326 GGUCAACAGCCAGCGGCCCtt SEQ ID NO: 2327CAGCCAGCGGCCCUUUAAUtt SEQ ID NO: 2328 UGCAGAGCCUCCCCCUGAGtt SEQ ID NO:2329 AACUACAUCACACCCAACCtt SEQ ID NO: 2330 CUACAUCACACCCAACCCUtt SEQ IDNO: 2331 CCCUAUCUUCUUCACCCGGtt SEQ ID NO: 2332 CCAUCUGCCUGUACCUAACtt SEQID NO: 2333 CCUGGAUCCAGACACCUAUtt SEQ ID NO: 2334 CUUUCCCAGGUACGAGAUCttSEQ ID NO: 2335 CCGACGCUCUGAGAUGACUtt SEQ ID NO: 2336AGAAGUAAAAGGUCUGGAGtt SEQ ID NO: 2337 GUAAAAGGUCUGGAGUGGAtt SEQ ID NO:2338 AAGGUCUGGAGUGGAGAACtt SEQ ID NO: 2339 GGUCUGGAGUGGAGAACAGtt SEQ IDNO: 2340 CAGGAGCCAUCAGCACUGCtt SEQ ID NO: 2341 CUCUGUGAAACUGAGGCCCtt SEQID NO: 2342 ACUGAGGCCCACGUCUGCUtt SEQ ID NO: 2343 GCUGAGGUCCUGCUGGCAUttSEQ ID NO: 2344 UGGGCAGCCUCUGCCACGUtt SEQ ID NO: 2345AUGGCUGGGCAGAGUGAGUtt SEQ ID NO: 2346 AGUUACAGCCACUGGCAACtt SEQ ID NO:2347 CGGCGGGAUUACAAAGGCUtt SEQ ID NO: 2348 AGGCUUCUCUCCAUCUGUGtt SEQ IDNO: 2349 CUUCCUGUCCAGUCGGCCAtt SEQ ID NO: 2350 UCAGGGGAGGUGACCAUCAtt SEQID NO: 2351 GGGCUAUGCAUGGAGUGGUtt SEQ ID NO: 2352 CCUGGCAGGUGGCUAAGCUttSEQ ID NO: 2353 GCUGGAUGGAGAGGAACAGtt SEQ ID NO: 2354CAGCGCCCCAGGAAGGCCUtt SEQ ID NO: 2355 GGCCUGGGCAUGGCGUCUGtt SEQ ID NO:2356 AGCCCCUGUGCCAGCUGGAtt SEQ ID NO: 2357 AAGGAACUGAACAUUGUUUtt SEQ IDNO: 2358 GGAACUGAACAUUGUUUGUtt SEQ ID NO: 2359 CUGAACAUUGUUUGUAAGGtt SEQID NO: 2360 CAUUGUUUGUAAGGCUGUGtt SEQ ID NO: 2361 GGCUGUGGAUGAUGGUUACttSEQ ID NO: 2362 UGUGCAGCCAGACACCGUGtt SEQ ID NO: 2363UCUGGAACCUGCGAGGUGUtt SEQ ID NO: 2364 CCUGCGAGGUGUUCUCAGCtt SEQ ID NO:2365 UGCCUGGCAUCGUGUCCAUtt SEQ ID NO: 2366 AGGAGCCACCUCCACCCCUtt SEQ IDNO: 2367 AAAUCUUUCCCACCUUUCAtt SEQ ID NO: 2368 AUCUUUCCCACCUUUCAACtt SEQID NO: 2369 CUUCUUGGAUCACAACUCUtt SEQ ID NO: 2370 CUCUGGCCUUCCUAAGCCAttSEQ ID NO: 2371 GCCAUACCCAAGUACACAUtt SEQ ID NO: 2372GUACACAUAUAGCACAUUUtt SEQ ID NO: 2373 GGACCUUCCCUCUUUGGACtt SEQ ID NO:2374 CCUGUGCCAGGAAGUGUGAtt SEQ ID NO: 2375 GUGUGAGCUGUUACAGCAAtt SEQ IDNO: 2376 GGGGCUAGAAGUGAAAAAAtt SEQ ID NO: 2377 GUGAAAAAAGUAAUUCUGGtt SEQID NO: 2378 AAAAGUAAUUCUGGAGACAtt SEQ ID NO: 2379 AAGUAAUUCUGGAGACAAGttSEQ ID NO: 2380 GUAAUUCUGGAGACAAGCAtt SEQ ID NO: 2381UUCUGGAGACAAGCACUAUtt SEQ ID NO: 2382 GCACUAUUUUCUCUUCCUAtt SEQ ID NO:2383 UGCCUACUGCCAUCAAGGCtt SEQ ID NO: 2384 GGCCUUGUUUUGCUUUUCUtt SEQ IDNO: 2385 AUGUGUGUGGCAUGUGUAAtt SEQ ID NO: 2386 GAAAAGUGUAUAUACUAUCtt SEQID NO: 2387 AAGUGUAUAUACUAUCUUAtt SEQ ID NO: 2388 GUGUAUAUACUAUCUUAUAttSEQ ID NO: 2389 GGGGCACAACCGUCUCCCUtt SEQ ID NO: 2390CCGUCUCCCUUUAUAGUUCtt SEQ ID NO: 2391 UAAAUAGUCUGUUUAAGAUtt SEQ ID NO:2392 AUAGUCUGUUUAAGAUCAUtt SEQ ID NO: 2393 GAUCAUAAAAAAAAAAAAAtt SEQ IDNO: 2394 AAAAAAAAAAAAAAAAAAAtt SEQ ID NO: 2395 AGGGGCGGGGCCAGCGCCGtt SEQID NO: 2396 ACCAGCCCAGCUCUGCGAGtt SEQ ID NO: 2397 UGUCUUCAGCACUGCAAUUttSEQ ID NO: 2398 AGUGUCUUCAGCACUGCAAtt SEQ ID NO: 2399GCAGACCGGGUCCAGUGUCtt SEQ ID NO: 2400 GCUCUGUGCAGCAGCAGCAtt SEQ ID NO:2401 ACUUGAGUCUGCAGGCCUGtt SEQ ID NO: 2402 GAUCCUUGAGGGGAUUGACtt SEQ IDNO: 2403 AUGCAGAUCCUUGAGGGGAtt SEQ ID NO: 2404 CAGGCCUGAAUGCAGAUCCtt SEQID NO: 2405 UGGGGCUGAAAUGAAUCAUtt SEQ ID NO: 2406 CCAUCCCUGGGUGCUGGAGttSEQ ID NO: 2407 UCCUUAGUGUAUAUGUGUGtt SEQ ID NO: 2408GUGGGAACUCACUUCCUCCtt SEQ ID NO: 2409 GGCUGGUGUGGGAACUCACtt SEQ ID NO:2410 CUGGAUGUAGGUCCACAAAtt SEQ ID NO: 2411 CCAGCUGCUAGCAUCAGCUtt SEQ IDNO: 2412 CUCACGCACAUGGGACUGGtt SEQ ID NO: 2413 AGGAUUCAGCUCCCCAAUCtt SEQID NO: 2414 GGCUACCUUGUCUUCAGGAtt SEQ ID NO: 2415 CGGUGGGGGCUACCUUGUCttSEQ ID NO: 2416 CUCCACGGUGGGGGCUACCtt SEQ ID NO: 2417GGGCCGCUGGCUGUUGACCtt SEQ ID NO: 2418 AUUAAAGGGCCGCUGGCUGtt SEQ ID NO:2419 CUCAGGGGGAGGCUCUGCAtt SEQ ID NO: 2420 GGUUGGGUGUGAUGUAGUUtt SEQ IDNO: 2421 AGGGUUGGGUGUGAUGUAGtt SEQ ID NO: 2422 CCGGGUGAAGAAGAUAGGGtt SEQID NO: 2423 GUUAGGUACAGGCAGAUGGtt SEQ ID NO: 2424 AUAGGUGUCUGGAUCCAGGttSEQ ID NO: 2425 GAUCUCGUACCUGGGAAAGtt SEQ ID NO: 2426AGUCAUCUCAGAGCGUCGGtt SEQ ID NO: 2427 CUCCAGACCUUUUACUUCUtt SEQ ID NO:2428 UCCACUCCAGACCUUUUACtt SEQ ID NO: 2429 GUUCUCCACUCCAGACCUUtt SEQ IDNO: 2430 CUGUUCUCCACUCCAGACCtt SEQ ID NO: 2431 GCAGUGCUGAUGGCUCCUGtt SEQID NO: 2432 GGGCCUCAGUUUCACAGAGtt SEQ ID NO: 2433 AGCAGACGUGGGCCUCAGUttSEQ ID NO: 2434 AUGCCAGCAGGACCUCAGCtt SEQ ID NO: 2435ACGUGGCAGAGGCUGCCCAtt SEQ ID NO: 2436 ACUCACUCUGCCCAGCCAUtt SEQ ID NO:2437 GUUGCCAGUGGCUGUAACUtt SEQ ID NO: 2438 AGCCUUUGUAAUCCCGCCGtt SEQ IDNO: 2439 CACAGAUGGAGAGAAGCCUtt SEQ ID NO: 2440 UGGCCGACUGGACAGGAAGtt SEQID NO: 2441 UGAUGGUCACCUCCCCUGAtt SEQ ID NO: 2442 ACCACUCCAUGCAUAGCCCttSEQ ID NO: 2443 AGCUUAGCCACCUGCCAGGtt SEQ ID NO: 2444CUGUUCCUCUCCAUCCAGCtt SEQ ID NO: 2445 AGGCCUUCCUGGGGCGCUGtt SEQ ID NO:2446 CAGACGCCAUGCCCAGGCCtt SEQ ID NO: 2447 UCCAGCUGGCACAGGGGCUtt SEQ IDNO: 2448 AAACAAUGUUCAGUUCCUUtt SEQ ID NO: 2449 ACAAACAAUGUUCAGUUCCtt SEQID NO: 2450 CCUUACAAACAAUGUUCAGtt SEQ ID NO: 2451 CACAGCCUUACAAACAAUGttSEQ ID NO: 2452 GUAACCAUCAUCCACAGCCtt SEQ ID NO: 2453CACGGUGUCUGGCUGCACAtt SEQ ID NO: 2454 ACACCUCGCAGGUUCCAGAtt SEQ ID NO:2455 GCUGAGAACACCUCGCAGGtt SEQ ID NO: 2456 AUGGACACGAUGCCAGGCAtt SEQ IDNO: 2457 AGGGGUGGAGGUGGCUCCUtt SEQ ID NO: 2458 UGAAAGGUGGGAAAGAUUUtt SEQID NO: 2459 GUUGAAAGGUGGGAAAGAUtt SEQ ID NO: 2460 AGAGUUGUGAUCCAAGAAGttSEQ ID NO: 2461 UGGCUUAGGAAGGCCAGAGtt SEQ ID NO: 2462AUGUGUACUUGGGUAUGGCtt SEQ ID NO: 2463 AAAUGUGCUAUAUGUGUACtt SEQ ID NO:2464 GUCCAAAGAGGGAAGGUCCtt SEQ ID NO: 2465 UCACACUUCCUGGCACAGGtt SEQ IDNO: 2466 UUGCUGUAACAGCUCACACtt SEQ ID NO: 2467 UUUUUUCACUUCUAGCCCCtt SEQID NO: 2468 CCAGAAUUACUUUUUUCACtt SEQ ID NO: 2469 UGUCUCCAGAAUUACUUUUttSEQ ID NO: 2470 CUUGUCUCCAGAAUUACUUtt SEQ ID NO: 2471UGCUUGUCUCCAGAAUUACtt SEQ ID NO: 2472 AUAGUGCUUGUCUCCAGAAtt SEQ ID NO:2473 UAGGAAGAGAAAAUAGUGCtt SEQ ID NO: 2474 GCCUUGAUGGCAGUAGGCAtt SEQ IDNO: 2475 AGAAAAGCAAAACAAGGCCtt SEQ ID NO: 2476 UUACACAUGCCACACACAUtt SEQID NO: 2477 GAUAGUAUAUACACUUUUCtt SEQ ID NO: 2478 UAAGAUAGUAUAUACACUUttSEQ ID NO: 2479 UAUAAGAUAGUAUAUACACtt SEQ ID NO: 2480AGGGAGACGGUUGUGCCCCtt SEQ ID NO: 2481 GAACUAUAAAGGGAGACGGtt SEQ ID NO:2482 AUCUUAAACAGACUAUUUAtt SEQ ID NO: 2483 AUGAUCUUAAACAGACUAUtt SEQ IDNO: 2484 UUUUUUUUUUUUUAUGAUCtt SEQ ID NO: 2485 UUUUUUUUUUUUUUUUUUUtt SEQID NO: 2486 CGGCGCUGGCCCCGCCCCUtt SEQ ID NO: 2487 CUCGCAGAGCUGGGCUGGUttSEQ ID NO: 2488 AAUUGCAGUGCUGAAGACAtt SEQ ID NO: 2489UUGCAGUGCUGAAGACACUtt SEQ ID NO: 2490 GACACUGGACCCGGUCUGCtt SEQ ID NO:2491 UGCUGCUGCUGCACAGAGCtt SEQ ID NO: 2492 CAGGCCUGCAGACUCAAGUtt SEQ IDNO: 2493 GUCAAUCCCCUCAAGGAUCtt SEQ ID NO: 2494 UCCCCUCAAGGAUCUGCAUtt SEQID NO: 2495 GGAUCUGCAUUCAGGCCUGtt SEQ ID NO: 2496 AUGAUUCAUUUCAGCCCCAttSEQ ID NO: 2497 CUCCAGCACCCAGGGAUGGtt SEQ ID NO: 2498CACACAUAUACACUAAGGAtt SEQ ID NO: 2499 GGAGGAAGUGAGUUCCCACtt SEQ ID NO:2500 GUGAGUUCCCACACCAGCCtt SEQ ID NO: 2501 UUUGUGGACCUACAUCCAGtt SEQ IDNO: 2502 AGCUGAUGCUAGCAGCUGGtt SEQ ID NO: 2503 CCAGUCCCAUGUGCGUGAGtt SEQID NO: 2504 GAUUGGGGAGCUGAAUCCUtt SEQ ID NO: 2505 UCCUGAAGACAAGGUAGCCttSEQ ID NO: 2506 GACAAGGUAGCCCCCACCGtt SEQ ID NO: 2507GGUAGCCCCCACCGUGGAGtt SEQ ID NO: 2508 GGUCAACAGCCAGCGGCCCtt SEQ ID NO:2509 CAGCCAGCGGCCCUUUAAUtt SEQ ID NO: 2510 UGCAGAGCCUCCCCCUGAGtt SEQ IDNO: 2511 AACUACAUCACACCCAACCtt SEQ ID NO: 2512 CUACAUCACACCCAACCCUtt SEQID NO: 2513 CCCUAUCUUCUUCACCCGGtt SEQ ID NO: 2514 CCAUCUGCCUGUACCUAACttSEQ ID NO: 2515 CCUGGAUCCAGACACCUAUtt SEQ ID NO: 2516CUUUCCCAGGUACGAGAUCtt SEQ ID NO: 2517 CCGACGCUCUGAGAUGACUtt SEQ ID NO:2518 AGAAGUAAAAGGUCUGGAGtt SEQ ID NO: 2519 GUAAAAGGUCUGGAGUGGAtt SEQ IDNO: 2520 AAGGUCUGGAGUGGAGAACtt SEQ ID NO: 2521 GGUCUGGAGUGGAGAACAGtt SEQID NO: 2522 CAGGAGCCAUCAGCACUGCtt SEQ ID NO: 2523 CUCUGUGAAACUGAGGCCCttSEQ ID NO: 2524 ACUGAGGCCCACGUCUGCUtt SEQ ID NO: 2525GCUGAGGUCCUGCUGGCAUtt SEQ ID NO: 2526 UGGGCAGCCUCUGCCACGUtt SEQ ID NO:2527 AUGGCUGGGCAGAGUGAGUtt SEQ ID NO: 2528 AGUUACAGCCACUGGCAACtt SEQ IDNO: 2529 CGGCGGGAUUACAAAGGCUtt SEQ ID NO: 2530 AGGCUUCUCUCCAUCUGUGtt SEQID NO: 2531 CUUCCUGUCCAGUCGGCCAtt SEQ ID NO: 2532 UCAGGGGAGGUGACCAUCAttSEQ ID NO: 2533 GGGCUAUGCAUGGAGUGGUtt SEQ ID NO: 2534CCUGGCAGGUGGCUAAGCUtt SEQ ID NO: 2535 GCUGGAUGGAGAGGAACAGtt SEQ ID NO:2536 CAGCGCCCCAGGAAGGCCUtt SEQ ID NO: 2537 GGCCUGGGCAUGGCGUCUGtt SEQ IDNO: 2538 AGCCCCUGUGCCAGCUGGAtt SEQ ID NO: 2539 AAGGAACUGAACAUUGUUUtt SEQID NO: 2540 GGAACUGAACAUUGUUUGUtt SEQ ID NO: 2541 CUGAACAUUGUUUGUAAGGttSEQ ID NO: 2542 CAUUGUUUGUAAGGCUGUGtt SEQ ID NO: 2543GGCUGUGGAUGAUGGUUACtt SEQ ID NO: 2544 UGUGCAGCCAGACACCGUGtt SEQ ID NO:2545 UCUGGAACCUGCGAGGUGUtt SEQ ID NO: 2546 CCUGCGAGGUGUUCUCAGCtt SEQ IDNO: 2547 UGCCUGGCAUCGUGUCCAUtt SEQ ID NO: 2548 AGGAGCCACCUCCACCCCUtt SEQID NO: 2549 AAAUCUUUCCCACCUUUCAtt SEQ ID NO: 2550 AUCUUUCCCACCUUUCAACttSEQ ID NO: 2551 CUUCUUGGAUCACAACUCUtt SEQ ID NO: 2552CUCUGGCCUUCCUAAGCCAtt SEQ ID NO: 2553 GCCAUACCCAAGUACACAUtt SEQ ID NO:2554 GUACACAUAUAGCACAUUUtt SEQ ID NO: 2555 GGACCUUCCCUCUUUGGACtt SEQ IDNO: 2556 CCUGUGCCAGGAAGUGUGAtt SEQ ID NO: 2557 GUGUGAGCUGUUACAGCAAtt SEQID NO: 2558 GGGGCUAGAAGUGAAAAAAtt SEQ ID NO: 2559 GUGAAAAAAGUAAUUCUGGttSEQ ID NO: 2560 AAAAGUAAUUCUGGAGACAtt SEQ ID NO: 2561AAGUAAUUCUGGAGACAAGtt SEQ ID NO: 2562 GUAAUUCUGGAGACAAGCAtt SEQ ID NO:2563 UUCUGGAGACAAGCACUAUtt SEQ ID NO: 2564 GCACUAUUUUCUCUUCCUAtt SEQ IDNO: 2565 UGCCUACUGCCAUCAAGGCtt SEQ ID NO: 2566 GGCCUUGUUUUGCUUUUCUtt SEQID NO: 2567 AUGUGUGUGGCAUGUGUAAtt SEQ ID NO: 2568 GAAAAGUGUAUAUACUAUCttSEQ ID NO: 2569 AAGUGUAUAUACUAUCUUAtt SEQ ID NO: 2570GUGUAUAUACUAUCUUAUAtt SEQ ID NO: 2571 GGGGCACAACCGUCUCCCUtt SEQ ID NO:2572 CCGUCUCCCUUUAUAGUUCtt SEQ ID NO: 2573 UAAAUAGUCUGUUUAAGAUtt SEQ IDNO: 2574 AUAGUCUGUUUAAGAUCAUtt SEQ ID NO: 2575 GAUCAUAAAAAAAAAAAAAtt SEQID NO: 2576 AAAAAAAAAAAAAAAAAAAtt

EXAMPLE III

The information herein above can be applied clinically to patients fordiagnosing an increased susceptibility for developing T1D, andtherapeutic intervention. A preferred embodiment of the inventioncomprises clinical application of the information described herein to apatient. Diagnostic compositions, including microarrays, and methods canbe designed to identify the genetic alterations described herein innucleic acids from a patient to assess susceptibility for developingT1D. This can occur after a patient arrives in the clinic; the patienthas blood drawn, and using the diagnostic methods described herein, aclinician can detect a SNP in chromosome 12. The typical age range for apatient to be screened is between 9 and 12 years of age. The informationobtained from the patient sample, which can optionally be amplifiedprior to assessment, will be used to diagnose a patient with anincreased or decreased susceptibility for developing T1D. Kits forperforming the diagnostic method of the invention are also providedherein. Such kits comprise a microarray comprising at least one of theSNPs provided herein in and the necessary reagents for assessing thepatient samples as described above.

The identity of T1D-involved genes and the patient results will indicatewhich variants are present, and will identify those that possess analtered risk for developing T1D. The information provided herein allowsfor therapeutic intervention at earlier times in disease progressionthat previously possible. Also, as described herein above, RPS26 andother genes described on chromosome 12, provide a novel target for thedevelopment of new therapeutic agents efficacious for the treatment ofT1D. In particular, it would be desirable to block expression of RPS26in those patients that are more prone to develop the disease. In thisregard, the therapeutic siRNAs described herein can be used to blockexpression of the gene product based on the patient signal, therebyinhibiting the pancreatic β-cell destruction that occurs in T1D.

REFERENCES

-   1. Cucca F, Lampis R, Congia M, et al. A correlation between the    relative predisposition of MHC class II alleles to type 1 diabetes    and the structure of their proteins. Human molecular genetics 2001;    10(19):2025-37.-   2. Julier C, Hyer R N, Davies J, et al. Insulin-IGF2 region on    chromosome 11p encodes a gene implicated in HLA-DR4-dependent    diabetes susceptibility. Nature 1991; 354(6349):155-9.-   3. Barratt B J, Payne F, Lowe C E, et al. Remapping the insulin    gene/IDDM2 locus in type 1 diabetes. Diabetes 2004; 53(7):1884-9.-   4. Bell G I, Horita S, Karam J H. A polymorphic locus near the human    insulin gene is associated with insulin-dependent diabetes mellitus.    Diabetes 1984; 33(2):176-83.-   5. Bottini N, Musumeci L, Alonso A, et al. A functional variant of    lymphoid tyrosine phosphatase is associated with type I diabetes.    Nature genetics 2004; 36(4):337-8.-   6. Smyth D, Cooper J D, Collins J E, et al. Replication of an    association between the lymphoid tyrosine phosphatase locus    (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a    general autoimmunity locus. Diabetes 2004; 53(11):3020-3.-   7. Nistico L, Buzzetti R, Pritchard L E, et al. The CTLA-4 gene    region of chromosome 2q33 is linked to, and associated with, type 1    diabetes. Belgian Diabetes Registry. Human molecular genetics 1996;    5(7):1075-80.-   8. Ueda H, Howson J M, Esposito L, et al. Association of the T-cell    regulatory gene CTLA4 with susceptibility to autoimmune disease.    Nature 2003; 423(6939):506-11.-   9. Vella A, Cooper J D, Lowe C E, et al. Localization of a type 1    diabetes locus in the IL2RA/CD25 region by use of tag    single-nucleotide polymorphisms. American journal of human genetics    2005; 76(5):773-9.-   10. Leiter E H, Lee C H. Mouse models and the genetics of diabetes:    is there evidence for genetic overlap between type 1 and type 2    diabetes? Diabetes 2005; 54 Suppl 2:S151-8.-   11. Gunderson K L, Steemers F J, Lee G, Mendoza L G, Chee M S. A    genome-wide scalable SNP genotyping assay using microarray    technology. Nature genetics 2005; 37(5):549-54.-   12. Fisher R A. Statistical Methods for Research Workers. 1958;    Hafner, New York, ed. 13.-   13. de Bakker P I, McVean G, Sabeti P C, et al. A high-resolution    HLA and SNP haplotype map for disease association studies in the    extended human MHC. Nature genetics 2006; 38(10):1166-72.-   14. Hirschhorn J N, Lohmueller K, Byrne E, Hirschhorn K. A    comprehensive review of genetic association studies. Genet Med 2002;    4(2):45-61.-   15. Finn R D, Mistry J, Schuster-Bockler B, et al. Pfam: clans, web    tools and services. Nucleic acids research 2006; 34(Database    issue):D247-51.-   16. Cambi A, Figdor C G. Levels of complexity in pathogen    recognition by C-type lectins. Current opinion in immunology 2005;    17(4):345-51.

While certain of the preferred embodiments of the present invention havebeen described and specifically exemplified above, it is not intendedthat the invention be limited to such embodiments. It will be apparentto one skilled in the art that various changes and modifications can bemade therein without departing from the scope of the present invention,as set forth in the following claims.

What is claimed is:
 1. A method for identifying a combination of siRNAmolecules selected from the group disclosed Tables 5-10 effective fordown-regulating the expression of at least one protein selected from thegroup consisting of RAB5B, CDK2, SUOX, IKZF4, RPS26 and ERBB3,comprising: a) contacting a cell with an effective amount of at leasttwo siRNA molecules selected from the group disclosed in Tables 5-10; b)assessing the effect of said siRNAs on down regulation of at least RPS26expression relative to untreated cells.
 2. The method of claim 1,wherein said cells are selected from the group consisting of INS cells,PC12 cells, MING cells, pancreatic beta islet cells and alpha TC6 cells.3. The method of claim 2 wherein modulatory effects of said siRNAs on aparameter selected from the group consisting of insulin secretion,glucagon secretion and glucosamine induced beta cell apoptosis isdetermined.